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Background: Differences in Sex Development (DSD) is a heterogeneous group of congenital alterations that affect inner and/or outer primary sex characters. Although these conditions do not represent a mortality risk, they can have a severe psycho-emotional impact if not appropriately managed. The genetic changes that can give rise to DSD are diverse, from chromosomal alterations to single base variants involved in the sexual development network. Epidemiological studies about DSD indicate a global frequency of 1:4500–5500, which can increase to 1:200–300, including isolated anatomical defects. To our knowledge, this study is the first to describe epidemiological and genetic features of DSD in a cohort of Mexican patients of a third-level care hospital. Methods: Descriptive and retrospective cross-sectional study that analyzed DSD patients from 2015 to 2021 attended a Paediatric Hospital from Mexico City. Results: One hundred one patients diagnosed with DSD were registered and grouped into different entities according to the Chicago consensus statement and the diagnosis defined by the multidisciplinary group. Of the total, 54% of them belong to the chromosomal DSD classification, 16% belongs to 46, XX and 30% of them belongs to the 46, XY classification. Conclusion: The frequency for chromosomal DSDs was consistent with the literature; however, we found that DSD 46, XY is more frequent in our cohort, which may be due to the age of the patients captured, the characteristics of our study population, or other causes that depend on the sample size. [ABSTRACT FROM AUTHOR]

Background: Premature ovarian insufficiency (POI) is a clinical syndrome defined by loss of ovarian function before the age of 40 years, characterized by elevated serum gonadotropin levels and decreased estrogen levels with menstrual disturbance. POI can be natural or iatrogenic such as after chemotherapy, radiotherapy and surgery. Case presentation: In this study, we describe a successful live birth in a 31-year-old woman with POI and 46, XY Karyotype after being treated with chemotherapy and bone marrow transplant (BMT) for acute non-lymphocytic leukemia when she was 17 years old. With amenorrhea or oligomenorrhea for 11 years, her serum level of FSH was up to 35.0 IU/L and 53.0 IU/L taken 4 weeks apart, which can be diagnosed as POI. After controlled ovarian stimulation treatment for three cycles with different protocols and frozen-thawed embryo transfer (FET), she finally got a successful pregnancy and had a live birth later. Conclusions: This case report serves as a reminder that karyotype of peripheral blood may mislead the diagnosis as disorders of sex development (DSD). It also demonstrates that it is possible for a woman with chemotherapy and bone marrow transplant induced POI can have successful pregnancy and live birth with appropriate therapy. Furthermore, as age may plays a predominant role in fertility rather than residual ovarian reserve, active treatment may be concerned for women with POI at younger age. [ABSTRACT FROM AUTHOR]

Background: Disorders of sex development (DSD) are congenital disorders in which the development of the chromosomal, gonadal, or anatomical sex is atypical. Mutations in various genes can impede gonadal development, hormone synthesis, or hormone function and cause DSD. Methods: Exome sequencing was performed for two siblings with 46,XY DSD. All mutations identified by exome sequencing were confirmed by Sanger sequencing. Results: The 13-month-old younger sibling had a female appearance of the external genital with a clitoris that was assessed as Prader III and scored 2 in the external masculinization score evaluative test. The 16-year-old elder sibling had severe hypospadias. Exome sequencing revealed compound heterozygous mutations in exon 3 of DHH in the siblings with 46,XY DSD. The frameshift mutation (NM_021044.3: c.602delC) was derived from the father and was predicted to be deleterious. The (c.937G > T) substitution mutation was derived from the mother. Conclusions: Novel compound heterozygous mutations of DHH led to 46,XY DSD in two siblings. This study expands the phenotypic mutation spectra of DHH in patients with 46,XY DSD. [ABSTRACT FROM AUTHOR]

Background: At present, there is no specific research on the factors affecting the success rate of urethroplasty in patients with DSD. The purpose of this study is to explore the factors affecting the success of urethroplasty in DSD patients, and to provide some reference for the surgical treatment of DSD patients undergoing urethroplasty.Method: We reviewed patients with DSD who underwent urethroplasty from January 2016 to December 2019 retrospectively. Patients were divided into four groups: the successful group, the urethrocutaneous fistula group, the urethral diverticulum group, and the urethral stricture group. Risk factors were determined from the following data included the DSD classification, the age of first operation, length of urethral defect, degree of hypospadias, cryptorchidism, micropenis, gonad type, hormone therapy before operation, transposition of penis and scrotum, surgical strategy, urethral covering material, and postoperative catheter removal time. We explored the difference of each factor between four groups through the comparative study of single factor and multifactor logistic regression analysis of related factors.Result: 122 cases were enrolled in this group (n = 122), 12 cases were lost to follow-up. Median follow-up was 28 months (12-55 months).We found the success rate of operation decreased with longer urethral defect (B = - 0.473, P = 0.005). The success rate of operation was higher in staged operation and TPIT (TPIT = Transverse Preputial Island Tube operation)-related operation than primary operation (B = 1.238, P = 0.006) and TPIT-nonrelated operation (B = 2.293, P = 0.001). Although there was a significant difference between the age of the first operation and the occurrence of urethrocutaneous fistula (P = 0.006 < 0.05), there was no significant difference in logistic regression analysis (P = 0.161 > 0.05). The incidence of urethrocutaneous fistula was lower in TPIT-related operation than in TPIT-nonrelated operation (B = - 2.507, P = 0.000). The incidence of postoperative urethral diverticulum was lower in staged operation than in primary operation (B = - 1.737, P = 0.015).Conclusion: For patients with disorder of sex development undergoing urethroplasty, the length of urethral defect is an independent risk factor affecting both the success rate of operation and the urethrocutaneous fistula. The age of the first operation has a statistically significant effect on the occurrence of postoperative urethrocutaneous fistula, but it is not an independent factor. Urethrocutaneous fistula is less found in TPIT-related operation in the study. Staged operation is an independent protective factor for postoperative urethral diverticulum compared with one-stage operation but isn't related to urethrocutaneous fistula. [ABSTRACT FROM AUTHOR]

Background: Intersex describes a diversity of individuals with variations in sex characteristics (VSC), reflecting underlying differences in reproductive anatomy, hormones, and/or genes and chromosomes. With a shift towards socially-conscious clinical practices, genetic counsellors (GCs) are increasingly needing to provide comprehensive care to individuals with VSC and their families. However, the current quality of training provided to genetic counsellors on intersex health is unclear., Methods: Qualitative interviews were conducted between Jan-Feb 2021 with 20 current and graduated students of Canadian GC training programs to assess the quality of GC education on intersex health topics. An agency-based model of VSC health as proposed by Crocetti et al. was used to guide the inductive thematic data analysis., Results: Results revealed three key themes: limited discussions on psychosocial considerations when caring for intersex individuals, enthusiasm for integrating more intersex training into the curriculum, and personal initiative in ensuring equity and justice in the care of individuals with VSC., Conclusions: These findings demonstrate existing knowledge gaps in the GC curriculum, with a need to increase the profession's overall awareness on intersex issues. GC training programs have an opportunity to meet the desires of students while promoting person-centered and validating healthcare for the intersex community., (© 2024. The Author(s).)

Objective: To identify the pathogenic mechanism of the c.244G>T mutation in NR5A1 gene found in a Chinese patient with 46, XY disorders of sex development (DSD).Subjects and Methods: Genomic DNA was extracted from a Chinese 46, XY DSD patient. Targeted next-generation and Sanger sequencing were performed to investigate and validate the gene mutation causing 46, XY DSD, respectively. In silico tools were used to predict the pathogenicity of the variant. Dual luciferase reporter gene assay and minigene splicing reporter assay were used to identify the pathogenicity of the variant.Results: A novel heterozygous variant, c.244G>T (p.Ala82Ser), in NR5A1 gene was detected in the 46, XY DSD patient. Four of five silico tools predicting pathogenicity of missense variants indicated that the variant was pathogenic. However, in vitro functional study showed that p.Ala82Ser did not affect the transcriptional activity of NR5A1. In silico tools predicting the potential splicing loci revealed that c.244G>T led to aberrant splicing of NR5A1 RNA. Minigene splicing reporter assay confirmed that c.244G>T resulted in the deletion of exon2 or deletion of 19 nucleotides in 3' end of exon2.Conclusions: Mutation of c.244G>T in NR5A1 results in 46, XY DSD by inducing abnormal splicing of NR5A1 RNA instead of amino acid substitution of NR5A1. [ABSTRACT FROM AUTHOR]

Background: Mixed gonadal dysgenesis (MGD) is a subtype of the disorders of sex development (DSD) associated with sex chromosome abnormalities characterized by abnormal external genitalia, short stature, and primary amenorrhea. This disease is generally diagnosed from the neonatal stage to early childhood, and by puberty at the latest. Cases that are phenotypically female or those with ambiguous genitalia experience a high risk of gonadal tumor formation. As tumor risk is known to increase with age, prophylactic bilateral gonadectomy is recommended following early diagnosis.Case Presentation: Here we report a case of an adult Japanese woman diagnosed with MGD during treatment for a giant pelvic tumor. The patient initially visited a gynecology clinic during puberty for primary amenorrhea, at which time an abnormality was found with the external genitalia. However, a diagnosis of MGD was not made at this time, resulting in the development of a malignant gonadal germ cell tumor in adulthood.Conclusions: For early diagnosis of MGD and the prevention of gonadal tumor formation, it is essential that gynecologists fully understand MGD and other DSD. [ABSTRACT FROM AUTHOR]

Background: This study investigates the health-related quality of life (HRQOL) of female patients with congenital adrenal hyperplasia (CAH) in Malaysia. The objectives were to attain socio-demographic and medical data on these Malaysian females with CAH and establish their health-related quality of life (HRQOL) in comparison to age matched diabetic controls.Methods: A cross-sectional study was conducted over 6 months in the two main tertiary centres for CAH patients in Malaysia. Participants including 59 female-raised CAH patients (mean age ± SD = 16.3 ± 4.2 years, range 10-28 years) compared to 57 age-matched female diabetic patients (mean age ± SD = 16.5 ± 3.4 years, range 10-26 years). Socio-demographic and medical profiles was obtained through semi-structured interviews. HRQOL of participants were evaluated utilising validated, Malay translated questionnaires which were age appropriate: Pediatric Quality of Life Inventory (PedsQL v4.0) scales for Child (8-12) and Adolescent (13-18) and Medical Outcome Survey 36-item Short Form version. These were then compared to the diabetic controls.Results: The CAH participants consisted of children (ages 10-12 years, n = 12), adolescents (ages 13-17 years, n = 29) and adults (≥ 18 years, n = 18). The majority were Malays (64.4%) and had salt-wasting CAH (67.8%). There were no significant differences between the total mean score of the HRQOL of the combined children and adolescents CAH group (total mean score ± SD = 81.6 ± 17.9, 95% CI = 75.6-87.6) when compared to age-matched diabetic patients (total mean score ± SD = 80.8 ± 11.0, 95% CI = 77.0-84.5, P = 0.81, effect size = 0.05); no significant difference between the adult CAH and diabetic controls in the physical [median score (IQR) CAH vs diabetics; 49.3 (11.4) vs. 50.2 (6.1), P = 0.60, effect size = 0.09] and the mental composite scores [median score (IQR) CAH vs. diabetics; 47.8 (14.1) vs. 50.0 (10.8), P = 0.93, effect size = 0.01].Conclusions: The HRQOL of the Malaysian CAH cohort were comparable to the diabetic controls. [ABSTRACT FROM AUTHOR]

Background: Mastermind-like domain-containing 1 (MAMLD1) has previously been identified as a causative gene for "46,XY Disorders of Sex Development (DSD)". Recently, there has been some controversy regarding the causative role of MAMLD1 variations in DSDs. Here we describe a clinical series and review the reported cases to evaluate the role of MAMLD1 variants in children with 46,XY DSD. Cases of 46,XY DSD harbouring MAMLD1 variants from unrelated families were recruited from the Beijing Children's Hospital in China (N = 10) or identified through a literature search (N = 26). The clinical manifestations and genetic variants of all the patients were evaluated.Results: Hypospadias was the most prevalent phenotype among our 10 cases (8 out of 10 cases) and in all the previously reported ones. Central precocious puberty and isolated micropenis were observed for the first time. Among the 10 cases, nine variants were identified, including three nonsense (p.R356X, p.Q152X, and p.Q124X) and six missense (p.P334S, p.S662R, p.A421P,p.T992I, p.P542S, and p.R927L) variants. In silico analysis showed that the variants p.P334S, p.P542S, p.S662R, and p.R927Lmight lead to drastic changes in the interaction force of the amino acid chain and the flexibility of the spatial structure, and such changes may affect protein function.Conclusion: Patients with 46,XY DSD harbouring MAMLD1variants manifest a broad spectrum of phenotypes and mostly present with hypospadias. The six novel variants reported here enrich the mutation database and contribute to our understanding of the pathogenesis of 46,XY DSD. [ABSTRACT FROM AUTHOR]

Background: Disorders of sex development (DSD) have an estimated frequency of 0.5% of live births encompassing a variety of urogenital anomalies ranging from mild hypospadias to a discrepancy between sex chromosomes and external genitalia. In order to identify the underlying genetic etiology, we had performed exome sequencing in a subset of DSD cases with 46,XY karyotype and were able to identify the causative genetic variant in 35% of cases. While the genetic etiology was not ascertained in more than half of the cases, a large number of variants of unknown clinical significance (VUS) were identified in those exomes. Methods: To investigate the relevance of these VUS in regards to the patient's phenotype, we utilized a mouse model in which the presence of a Y chromosome from the poschiavinus strain (YPOS) on a C57BL/6J (B6) background results in XY undervirilization and sex reversal, a phenotype characteristic to a large subset of human 46,XY DSD cases. We assessed gene expression differences between B6-YB6 and undervirilized B6-YPOS gonads at E11.5 and identified 515 differentially expressed genes (308 underexpressed and 207 overexpressed in B6-YPOS males). Results: We identified 15 novel candidate genes potentially involved in 46,XY DSD pathogenesis by filtering the list of human VUS-carrying genes provided by exome sequencing with the list of differentially expressed genes from B6-YPOS mouse model. Additionally, we identified that 7 of the 15 candidate genes were significantly underexpressed in the XY gonads of mice with suppressed Sox9 expression in Sertoli cells suggesting that some of the candidate genes may be downstream of a well-known sex determining gene, Sox9. Conclusion: The use of a DSD-specific animal model improves variant interpretation by correlating human sequence variants with transcriptome variation. [ABSTRACT FROM AUTHOR]

Background: dsd-LIFE is a comprehensive cross-sectional clinical outcome study of individuals with disorders/differences of sex development (DSD). This study focuses on various rare genetic conditions characterized by impaired gonadal or adrenal functionality. Methods/Design: The study aims to assess quality of life (QoL) as a measure of psychosocial adaptation, psychosexual and mental health aspects as major outcomes. Health status and functioning, medical and surgical therapies, participants' views on health care, psychological and social support, sociodemographic factors and their interrelations will be investigated as factors associated with the outcomes. In addition, ethical considerations in the field of DSD are addressed and previous experiences with health care were gathered. One thousand and forty participants with different DSD conditions were recruited by 14 study centres in 6 European countries (France, Germany, the Netherlands, Poland, Sweden and the United Kingdom) from February 2014 until September 2015. The conditions included were: Turner syndrome ( n = 301); 45,X0/46,XY conditions ( n = 45); Klinefelter syndrome ( n = 218); 47,XYY ( n = 1); 46,XY gonadal dysgenesis/ovotestes ( n = 63); complete androgen insensitivity (CAIS) ( n = 71); partial androgen insensitivity (PAIS) ( n = 35) and androgen synthesis disorders ( n = 20); severe hypospadias ( n = 25); other or non-classified 46,XY DSD ( n = 8); 46,XX congenital adrenal hyperplasia (CAH) ( n = 226); 46,XX gonadal dysgenesis/ovotestis ( n = 21); and 46,XX in males ( n = 6). For an add-on study, 121 46,XY male-assigned individuals with CAH due to 21-hydroxylase deficiency were recruited. Mean age of participants' was 32.4 (+/− 13.6 years). Discussion: Participation was high in conditions not commonly described as DSD, such as Turner and Klinefelter syndromes or CAH. Recruitment of individuals with XY DSD conditions proved to be more difficult. The data collection of PROs resulted in high data quality. Within medical and physical examination data, more missings and/or inaccurate data were found than expected. The European dsd-LIFE study recruited and evaluated the largest cross-sectional sample of individuals with different conditions classified under the term DSD. The data from this large sample will provide a sufficient basis for evidence-based recommendations for improvement of clinical care of individuals affected by a DSD condition. Trial registration: German Clinical Trials Register . [ABSTRACT FROM AUTHOR]

Background: With the proliferation of rare disease registries, there is a need for registries to undergo an assessment of their quality against agreed standards to ensure their long-term sustainability and acceptability.This study was performed to evaluate the I-DSD and I-CAH Registries and identify their strengths and weaknesses.Methods: The design and operational aspects of the registries were evaluated against published quality indicators. Additional criteria included the level of activity, international acceptability of the registries and their use for research.Results: The design of the I-DSD and I-CAH Registries provides them with the ability to perform multiple studies and meet the standards for data elements, data sources and eligibility criteria. The registries follow the standards for data security, governance, ethical and legal issues, sustainability and communication of activities. The data have a high degree of validity, consistency and accuracy and the completeness is maximal for specific conditions such as androgen insensitivity syndrome and congenital adrenal hyperplasia. In terms of research output, the external validity is strong but the wide variety of cases needs further review. The internal validity of data was condition specific and highest for conditions such as congenital adrenal hyperplasia. The shift of the registry from a European registry to an international registry and the creation of a discrete but linked CAH registry increased the number of users and stakeholders as well as the international acceptability of both registries.Conclusions: The I-DSD and I-CAH registries comply with the standards set by expert organisations. Recent modifications in their operation have allowed the registries to increase their user acceptability. [ABSTRACT FROM AUTHOR]

Background: To explore the current models of practice in centres delivering specialist care for children with disorders of sex development (DSD), an international survey of 124 clinicians, identified through DSDnet and the I-DSD Registry, was performed in the last quarter of 2014. Results: A total of 78 (63 %) clinicians, in 75 centres, from 38 countries responded to the survey. A formal national network for managing DSD was reported to exist in 12 (32 %) countries. The paediatric specialists routinely involved in the initial evaluation of a newborn included: endocrinologist (99 %), surgeon/urologist (95 %), radiologist (93 %), neonatologist (91 %), clinical geneticist (81 %) and clinical psychologist (69 %). A team consisting of paediatric specialists in endocrinology, surgery/urology, clinical psychology, and nursing was only possible in 31 (41 %) centres. Of the 75 centres, 26 (35 %) kept only a local DSD registry and 40 (53 %) shared their data in a multicentre DSD registry. Attendance in local, national and international DSDrelated educational programs was reported by 69, 78 and 84 % clinicians, respectively. Participation in audits/quality improvement exercises in DSD care was reported by 14 (19 %) centres. In addition to complex biochemistry and molecular genetic investigations, 40 clinicians (51 %) also had access to next generation sequencing. A genetic test was reported to be more preferable than biochemical tests for diagnosing 5-alpha reductase deficiency and 17-beta hydroxysteroid dehydrogenase 3 deficiency by 50 and 55 % clinicians, respectively. Conclusion: DSD centres report a high level of interaction at an international level, have access to specialist staff and are increasingly relying on molecular genetics for routine diagnostics. The quality of care provided by these centres locally requires further exploration. [ABSTRACT FROM AUTHOR]

NR5A1 is the key regulator of adrenal and gonadal development in both humans and mice. Recently, a missense substitution in human NR5A1, p.R92W, was shown to underlie gonadal dysgenesis in genetic males and testicular formation in genetic females. Here, we investigated the phenotypic effects of the p.R92W mutation on murine development. Mice carrying the p.R92W mutation manifested a similar but milder phenotype than that of the previously described Nr5a1 knockout mice. Importantly, mutation-positive XX mice showed no signs of masculinization. These results, together with prior observations, indicate that the p.R92W mutation in NR5A1/Nr5a1 encodes unique molecules that disrupt male gonadal development in both humans and mice and induces testicular formation specifically in human females. Our findings provide novel insights into the conservation and divergence in the molecular networks underlying mammalian sexual development. [ABSTRACT FROM AUTHOR]

In pediatric patients, basal testosterone and gonadotropin levels may be uninformative in the assessment of testicular function. Measurement of serum anti-Müllerian hormone (AMH) has become increasingly widespread since it provides information about the activity of the male gonad without the need for dynamic tests, and also reflects the action of FSH and androgens within the testis. AMH is secreted in high amounts by Sertoli cells from fetal life until the onset of puberty. Basal AMH expression is not dependent on gonadotropins or sex steroids; however, FSH further increases and testosterone inhibits AMH production. During puberty, testosterone induces Sertoli cell maturation, and prevails over FSH on AMH regulation. Therefore, AMH production decreases. Serum AMH is undetectable in patients with congenital or acquired anorchidism, or with complete gonadal dysgenesis. Low circulating levels of AMH may reflect primary testicular dysfunction, e.g. in certain patients with cryptorchidism, monorchidism, partial gonadal dysgenesis, or central hypogonadism. AMH is low in boys with precocious puberty, but it increases to prepubertal levels after successful treatment. Conversely, serum AMH remains at high, prepubertal levels in boys with constitutional delay of puberty. Serum AMH measurements are useful, together with testosterone determination, in the diagnosis of patients with ambiguous genitalia: both are low in patients with gonadal dysgenesis, including ovotesticular disorders of sex development, testosterone is low but AMH is in the normal male range or higher in patients with disorders of androgen synthesis, and both hormones are normal or high in patients with androgen insensitivity. Finally, elevation of serum AMH above normal male prepubertal levels may be indicative of rare cases of sex-cord stromal tumors or Sertoli cell-limited disturbance in the McCune Albright syndrome. [ABSTRACT FROM AUTHOR]

Background: 17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) deficiency is a rare cause of disorder of sex development (DSD) due to impaired conversion of androstenedione to testosterone. Traditionally, the diagnosis was determined by βHCG-stimulated ratios of testosterone:androstenedione < 0.8. Case presentation: An otherwise phenotypically female infant presented with bilateral inguinal masses and a 46,XY karyotype. βHCG stimulation (1500 IU IM for 2 days) suggested 17βHSD3 deficiency although androstenedione was only minimally stimulated (4.5 nmol/L to 5.4 nmol/L). Expedient genetic testing for the HSD17B3 gene provided the unequivocal diagnosis. Conclusion: We advocate for urgent genetic testing in rare causes of DSD as indeterminate hormone results can delay diagnosis and prolong intervention. [ABSTRACT FROM AUTHOR]

Background: The identification of causative mutations is important for treatment decisions and genetic counseling of patients with disorders of sex development (DSD). Here, we designed a new assay based on targeted nextgeneration sequencing (NGS) to diagnose these genetically heterogeneous disorders. Methods: All coding regions and flanking sequences of 219 genes implicated in DSD were designed to be included on a panel. A total of 45 samples were used for sex chromosome dosage validation by targeted sequencing using the NGS platform. Among these, 21 samples were processed to find the causative mutation. Results: The sex chromosome dosages of all 45 samples in this assay were concordant with their corresponding karyotyping results. Among the 21 DSD patients, a total of 11 mutations in SRY, NR0B1, AR, CYP17A1, GK, CHD7, and SRD5A2 were identified, including five single nucleotide variants, three InDels, one in-frame duplication, one SRYpositive 46,XX, and one gross duplication with an estimated size of more than 427,038 bp containing NR0B1 and GK. We also identified six novel mutations: c.230_231insA in SRY, c.7389delA in CHD7, c.273C>G in NR0B1, and c.2158G>A, c.1825A>G, and c.2057_2065dupTGTGTGCTG in AR. Conclusions: Our assay was able to make a genetic diagnosis for eight DSD patients (38.1%), and identified variants of uncertain clinical significance in the other three cases (14.3%). Targeted NGS is therefore a comprehensive and efficient method to diagnose DSD. This work also expands the pathogenic mutation spectrum of DSD. [ABSTRACT FROM AUTHOR]

Background: Swyer syndrome is a rare manifestation of disorders of sex development in which the individual is 46, XY in genotype but phenotypically a female. They have normal female external genitalia with under developed female internal genitalia. They usually present with primary amenorrhoea and delayed puberty but also can present with gonadal tumors in adult life. Case presentation: A 25-year-old Sri Lankan phenotypically female having 46 XY karyotype with a history of primary amenorrhoea, presented with left loin pain associated with fever. General examination revealed a tall stature, scanty axillary and pubic hair, small breasts and clitoromegally. A tender ill-defined mass was detected in the left hypochondrial region. She had high erythrocyte sedimentation rate with elevated alkaline phosphatase and lactate dehydrogenase levels. Her serum hormonal assay revealed a low estradiol level with elevated luteinizing hormone and follicular stimulating hormone levels with normal progesterone and testosterone levels. Computerized tomography of abdomen showed a large complex mass lesion in relation to antero-medial aspect of the lower pole of the left kidney with para-aortic and left common iliac lymph nodes. The diagnostic laparoscopy confirmed the presence of internal female genitalia and the mass lesion was seen in left para-aortic region. The histology revealed a germ cell tumor compatible with a dysgerminoma. Conclusion: Patients with Swyer syndrome can present with gonadal tumors, typically a dysgerminoma in their adult life. [ABSTRACT FROM AUTHOR]

Background: Urinary steroid metabolite ratios may improve the diagnostic yield of potential disorders of steroid hormone synthesis. Objectives: To investigate the range of ratios and their predictive value in children with suspected disorders of steroid synthesis. Design and methods: Twelve ratios were calculated on steroid metabolite data analysed by gas chromatography-mass spectrometry in urine samples collected between 2008-2010 from 93 children. Urine samples were also analysed in 252 children with no known endocrine concerns. Results: Of the 252 controls, 115 (46%) were male with a median age of 10 yr (range 1 month, 18.5 years). Of the 93 cases, 38 (41%) were male with a median age of 6.5 yr (1 day,18.5 yrs). Of these, 41 (44%) had at least one ratio greater than the 95% percentile for controls. The most frequently abnormal ratio, found in 18/93 (19%) cases was (THS/(THE + THF + 5αTHF)) suggestive of 11β-hydroxylase deficiency. Over this period, 8 (9%) children were subsequently diagnosed with a steroid hormone disorder; 4 with 21-hydroxylase deficiency, 2 with11β-hydroxylase deficiency and 2 with 5α-reductase deficiency. All except one of these children had at least 1 raised ratio. Conclusions: Urinary steroid metabolite ratios in suspected disorders of hormone synthesis often exceed the reference range for normal children. The predictive value of steroid metabolite ratios in identifying a genetic abnormality may be condition specific and needs further study to improve its clinical utility. [ABSTRACT FROM AUTHOR]

Background: As the benefits of patient-centered care have become more widely recognized, it is important to understand patients' sentiments regarding aspects affecting their care. In an effort to display more sensitivity to patient concerns, the term "disorders of sex development" (DSD) was proposed in 2006 as new nomenclature to replace older terms that were considered to have negative connotations. Methods: The objective of the study was to examine the views of congenital adrenal hyperplasia (CAH) patients and their caregivers regarding the new nomenclature. The study was observational to evaluate the views of the CAH community, and the primary endpoint was perception of the term DSD. The study was conducted as a survey about views regarding DSD nomenclature. The survey was sent via email to eligible subjects. Along with a short introduction explaining the term DSD, the survey was sent to eligible CAH patients and their caregivers. 589 CAH patients or family members participated in the survey. Results: A total of 589 responses were received (255 classical females, 104 non-classical females, 174 males, 56 not specified) (547 U.S., 42 international) (128 CAH patients, 408 parents or other family members). 70.6% had never heard the term DSD. 71.0% disliked or strongly disliked the term DSD. 83.6% stated they did not identify with the term DSD. 76.0% felt that the term DSD has a negative effect on the CAH community. There was no significant difference in opinion of DSD between classical females and other CAH patients, between US and international, between surgical and non-surgical patients, or between patients and parents. There was no correlation with patient age. Conclusions: Our results indicate that the majority of parents and patients with CAH are dissatisfied with the term DSD. Our results highlight the challenges within the field of DSD to reach a consensus regarding a sensitive topic and to bridge the gap between current medical practice and patient satisfaction. It is the authors' belief that reconsideration of the current nomenclature and ongoing dialogue between the medical community and patients will eventually lead to removal of stigmatization, better management protocols, and improved outcomes. [ABSTRACT FROM AUTHOR]

Background Disorders of sex development (DSD) is the term used for congenital conditions in which development of chromosomal, gonadal, or phenotypic sex is atypical. Nuclear receptor subfamily 5, group A, member 1 gene (NR5A1) encodes steroidogenic factor 1 (SF1), a transcription factor that is involved in gonadal development and regulates adrenal steroidogenesis. Mutations in the NR5A1 gene may lead to different 46,XX or 46,XY DSD phenotypes with or without adrenal failure. We report a Brazilian family with a novel NR5A1 mutation causing ambiguous genitalia in 46,XY affected individuals without Müllerian derivatives and apparently normal Leydig function after birth and at puberty, respectively. Their mother, who is also heterozygous for the mutation, presents evidence of primary ovarian insufficiency. Case presentation Three siblings with 46,XY DSD, ambiguous genitalia and normal testosterone production were included in the study. Molecular analyses for AR, SRD5A2 genes did not reveal any mutation. However, NR5A2 sequence analysis indicated that all three siblings were heterozygous for the p.Cys65Tyr mutation which was inherited from their mother. In silico analysis was carried out to elucidate the role of the amino acid change on the protein function. After the mutation was identified, all sibs and the mother had been reevaluated. Basal hormone concentrations were normal except that ACTH levels were slightly elevated. After 1 mcg ACTH stimulation test, only the older sib showed subnormal cortisol response. Conclusion The p.Cys65Tyr mutation located within the second zinc finger of DNA binding domain was considered deleterious upon analysis with predictive algorithms. The identification of heterozygous individuals with this novel mutation may bring additional knowledge on structural modifications that may influence NR5A1 DNA-binding ability, and may also contribute to genotype-phenotype correlations in DSD. The slightly elevated ACTH basal levels in all three patients with 46,XY DSD and the subnormal cortisol response after 1 mcg ACTH stimulation in the older sib indicate that a long-term follow-up for adrenal function is important for these patients. Our data reinforce that NR5A1 analysis must also be performed in 46,XY DSD patients with normal testosterone levels without AR mutations. [ABSTRACT FROM AUTHOR]

Background: 17β-Hydroxysteroid dehydrogenase type-3 (17βHSD-3) deficiency is a rare cause of 46,XY disorders of sex development. The enzyme converts androstenedione to testosterone, necessary for masculinization of male genitalia in utero. 17βHSD-3 deficiency is frequently diagnosed late, at puberty, following virilization, with consequent female-to-male gender reassignment in 39-64%. The decision for sex of rearing is difficult, especially if diagnosed in early childhood. Consensus guidelines are equivocal or support male gender assignment. Long-term outcomes data to guide decisions are also lacking; however, in the few cases of early diagnosis and orchiectomy, female gender retention appears more likely. We report two patients with 17βHSD-3 deficiency, who presented at unusual ages, in whom female gender was chosen. We performed a focused literature review and summary of gender outcomes in 17βHSD-3 deficiency following early orchiectomy. Cases: Patient A was a phenotypic female who presented at one year of age with bilateral inguinal hernias and external female genitalia. Testes were identified at surgery. The karyotype was 46,XY. She was initially diagnosed with complete androgen insensitivity syndrome; however, androgen receptor mutation analysis was negative. Human chorionic gonadotropin stimulation yielded a low testosterone: androstenedione ratio (0.6, normal >0.8). Genetic testing demonstrated compound heterozygosity for two known mutations of the HSD17B3 gene. She underwent bilateral orchiectomy at two years of age. Patient B was born with female genitalia and virilized at 13 years of age. She did not seek evaluation until 22 years of age. Her karyotype was 46,XY. She had bilateral inguinal testes and low testosterone: androstenedione ratio (0.3). HSD17B3 gene sequencing showed her to be a compound heterozygote for two known mutations. She identified herself as female and underwent bilateral orchiectomy and estrogen replacement therapy. Conclusions: These two patients highlight the complexities of diagnosis and management in 17βHSD-3 deficiency. Although existing data are limited, early orchiectomy is likely to result in retention of female gender identity, avoiding the complications related to virilization in adolescence. As such, it is important to pursue a definitive diagnosis to guide clinical decisions, and to have the support and long term follow up with an inter-disciplinary disorders of sex development team. [ABSTRACT FROM AUTHOR]

Sexual development in humans is only partly understood at the molecular level. It is dependent on genetic control primarily induced by the sex chromosomal differences between males and females. This leads to the development of the gonads, whereby afterwards the differentiation of the apparent phenotype is controlled by hormone action. Sex steroids may exert permanent and temporary effects. Their organizational features of inducing permanent changes in phenotype occur through genetic control of downstream genes. In this, androgens are the key elements for the differentiation of male internal and external genitalia as well as other sexual organs and general body composition, acting through a single androgen receptor. The androgen receptor is a nuclear transcription factor modulating DNA transcription of respective target genes and thereby driving development and growth in a stringent manner. The specificity of androgen action seems to be a strictly time-controlled process with the androgen receptor acting in concert with different metabolites and an array of cofactors modulating the cellular response and thereby permanently altering the phenotype of any given individual. For every cell programmed by androgens, a specific 'androgen response index' must be proposed. [ABSTRACT FROM AUTHOR]

Background: The expression and biological functions of circular RNAs (circRNAs) in reproductive organs have been extensively reported. However, it is still unclear whether circRNAs are involved in sex change. To this end, RNA sequencing (RNA-seq) was performed in gonads at 5 sexual stages (ovary, early intersexual stage gonad, middle intersexual stage gonad, late intersexual stage gonad, and testis) of ricefield eel, and the expression profiles and potential functions of circRNAs were studied., Results: Seven hundred twenty-one circRNAs were identified, and the expression levels of 10 circRNAs were verified by quantitative real-time PCR (qRT-PCR) and found to be in accordance with the RNA-seq data, suggesting that the RNA-seq data were reliable. Then, the sequence length, category, sequence composition and the relationship between the parent genes of the circRNAs were explored. A total of 147 circRNAs were differentially expressed in the sex change process, and GO and KEGG analyses revealed that some differentially expressed (such as novel&#95;circ&#95;0000659, novel&#95;circ&#95;0004005 and novel&#95;circ&#95;0005865) circRNAs were closely involved in sex change. Furthermore, expression pattern analysis demonstrated that both circSnd1 and foxl2 were downregulated in the process of sex change, which was contrary to mal-miR-135b. Finally, dual-luciferase reporter assay and RNA immunoprecipitation showed that circSnd1 and foxl2 can combine with mal-miR-135b and mal-miR-135c. These data revealed that circSnd1 regulates foxl2 expression in the sex change of ricefield eel by acting as a sponge of mal-miR-135b/c., Conclusion: Our results are the first to demonstrate that circRNAs have potential effects on sex change in ricefield eel; and circSnd1 could regulate foxl2 expression in the sex change of ricefield eel by acting as a sponge of mal-miR-135b/c. These data will be useful for enhancing our understanding of sequential hermaphroditism and sex change in ricefield eel or other teleosts., (© 2022. The Author(s).)

Background: An increasing number of long noncoding RNAs (lncRNAs) have been found to play important roles in sex differentiation and gonad development by regulating gene expression at the epigenetic, transcriptional and posttranscriptional levels. The ricefield eel, Monopterus albus, is a protogynous hermaphroditic fish that undergoes a sequential sex change from female to male. However, the roles of lncRNA in the sex change is unclear., Results: Herein, we performed RNA sequencing to analyse lncRNA expression patterns in five different stages of M. albus development to investigate the roles of lncRNAs in the sex change process. A total of 12,746 lncRNAs (1503 known lncRNAs and 11,243 new lncRNAs) and 2901 differentially expressed lncRNAs (DE-lncRNAs) were identified in the gonads. The target genes of the DE-lncRNAs included foxo1, foxm1, smad3, foxr1, camk4, ar and tgfb3, which were mainly enriched in signalling pathways related to gonadal development, such as the insulin signalling pathway, MAPK signalling pathway, and calcium signalling pathway. We selected 5 highly expressed DE-lncRNAs (LOC109952131, LOC109953466, LOC109954337, LOC109954360 and LOC109958454) for full length amplification and expression pattern verification. They were all expressed at higher levels in ovaries and intersex gonads than in testes, and exhibited specific time-dependent expression in ovarian tissue incubated with follicle-stimulating hormone (FSH) and human chorionic gonadotropin (hCG). The results of quantitative real-time PCR (qRT-PCR) analysis and a dual-luciferase assay showed that znf207, as the gene targeted by LOC109958454, was expressed in multiple tissues and gonadal developmental stages of M. albus, and its expression was also inhibited by the hormones FSH and hCG., Conclusions: These results provide new insights into the role of lncRNAs in gonad development, especially regarding natural sex changes in fish, which will be useful for enhancing our understanding of sequential hermaphroditism and sex changes in the ricefield eel (M. albus) and other teleosts., (© 2022. The Author(s).)

Background: The Congenital Adrenal Hyperplasia due to 21 hydroxylase deficiency is the most common cause of genital ambiguity in persons with XX sexual chromosomes. Genital ambiguity among persons with XY sexual chromosomes comprises diverse and rare etiologies. The deficiency of 17-beta-hydroxysteroid dehydrogenase type 3 enzyme (HSD17B3) is a rare autosomal recessive disorder due to functionally altered variants of the HSD17B3 gene. In this disorder/difference of sex development, the conversion of androstenedione into testosterone is impaired. The appearance of external genitalia of 46,XY individuals varies from typically male to almost female., Case Presentation: We report on a child presenting severe ambiguous genitalia. Due to access constraints, specialized care did not start until the child was 10 months old. Parents are consanguineous and were born in an area of high isonymy that is a cluster for rare recessive diseases. A new homozygous missense variant c.785G > T was found in exon 10 of the HSD17B3 gene., Conclusions: Researchers-clinicians and researchers-researchers collaborative efforts to elucidate the genetic basis of this disease were critical since this etiologic investigation is not available through the public health system. This case exemplifies the families' pilgrimage in cases of genital ambiguity due to a rare genetic condition. Recognizing the etiology was the baseline to provide information on prognosis and treatment options, and to shelter family and child doubts and hopes in order to better support their decisions., (© 2022. The Author(s).)

Background: 49XXXXY syndrome is the rarest X chromosome aneuploidy, with approximate incidence of 1:85,000-100,000 male births. Worldwide, around 100 cases have been reported. In this report, we describe one such case seen in Sri Lanka., Case Presentation: A 10-day-old Sri Lankan neonate born in a tertiary care center was referred to the pediatric endocrinology unit of Lady Ridgeway Hospital due to detection of ambiguous genitalia at birth. He was the first child born to nonconsanguineous healthy parents following an uncomplicated antenatal period. He was born at term via normal vaginal delivery, with a birth weight of 2.385 kg. The baby was active, and there was no documented hypoglycemia or alteration in basic biochemical investigations. On examination, the child had hypertelorism, upslanting palpebral fissures, flat occiput, and mild webbing of the neck. System examination was normal. Genitalia examination revealed bifid scrotum, perineal urethra, 2 cm phallus, and bilateral testis in situ. Hormonal analysis, including dehydroepiandrosterone sulfate, testosterone, and 17-OH progesterone levels, was normal except for an elevated level of follicle-stimulating hormone, indicating gonadal dysgenesis. Ultrasound of the abdomen detected testis located at bilateral inguinal canal, and no Müllerian structures were visible. Echocardiography showed a small patent foramen ovale with otherwise normal heart. Chromosome analysis revealed 49XXXXY syndrome., Conclusion: 49XXXXY syndrome should be entertained as a rare possibility for ambiguous genitalia, and karyotyping is an essential investigation for evaluation of such patients., (© 2021. The Author(s).)

Background: Expression of sexual dimorphism is recognised in various fossil groups of molluscs such as the Ammonoidea, an extinct group of shelled cephalopods. During the Mesozoic, the best-documented sexual dimorphic examples are seen in the Jurassic superfamily Perisphinctoidea. It is usually expressed by distinct adult size and apertural modifications between the antidimorphs. Putative males (otherwise referred to as microconch) are small in size and develop lappets at the end of the shell while the females (macroconch) are larger and bear a simple peristome. Dubious cases are, however, known in that superfamily, which often relate to taxonomic biases or lack of diagnostic characters, and some others expose ontogenetic anomalies illustrated by 'sex reversals' in the shell morphology and ornamentation., Results: The discovery of two specimens of the Callovian Aspidoceratidae Peltoceras athleta (Phillips), having both female and male features, questions the significance and causes of 'sex reversals' in the Ammonoidea. The two specimens have started with the macroconch ontogeny of Peltoceras athleta and show an apparent change toward maleness in the adult, as illustrated by their rounded whorl section, ribs retroversion, fading of the tubercles and lappets typical of the microconchs. Few other cases of female-to-male, as well as male-to-female 'sex reversal', are known in the fossil record, all belonging to the Jurassic Perisphinctoidea (families Perisphinctidae or Aspidoceratidae). Since all Jurassic Perisphinctoidea are strictly gonochoristic, these 'sex reversals' are pathological in nature and are herein referred to as a new forma-type pathology: namely "forma hermaphrodita"., Conclusions: In the absence of any clear evidence of injury or parasitism, we hypothesize that such "forma hermaphrodita" individuals illustrate pathologic cases of intersexuality. Little is known about the ammonoid soft parts, and it is not possible to determine which internal sexual organs occur in specimens having both male and female external shell features. Abnormal feminisation and/or masculinisation also occur in modern cephalopods, the latter also grouping only gonochoric species. This phenomenon is similarly illustrated by a change in the adult body size and a mixing of both female and male structures. In that case, intersexuality is either advantageous in the population or caused sterility. The causes of intersexuality are not clearly established but environmental pollutants are evoked in modern cephalopods because they act as endocrine disrupters. 'Sex reversals' and/or non-functional reproductive abnormalities have also been caused by endocrine disrupters in various gonochoric gastropods species, but infestation, genetic abnormalities, temperature fluctuations or viruses are multiple causes, which can stimulate or inhibit neural-endocrinal activity by direct gonadal influence, and ultimately lead to feminisation or masculinisation in fishes, isopods, crustaceans, and gastropods as well. Regardless of whether "forma hermaphrodita" is due to an exogenic or endogenic cause, the record of intersex Perisphinctoidea in the Jurassic can be explained by the ready recognition of dimorphic pairs, and the easy collection of large and sufficiently preserved fossil palaeopopulations in which intersex specimens have statistically more chance to be found.

Background: The Differences of Sex Development network (DSDnet) aims to establish interactive relationships between clinicians, scientists, support groups and people with a difference of sex development (DSD) to improve the overall care for people affected by such condition. DSDnet has hosted three Training Schools (TSs) in Ghent, Bologna and Budapest between 2015 and 2017 with the primary purpose of providing multidisciplinary training to young professionals and encouraging ongoing activity in the field of DSD. The aim of our study was to evaluate the success and long-term effect effectiveness of these three TSs., Methods and Results: Eighty-seven trainees (70 women, 17 men) attended one of three TSs. The distribution of trainees according to their professional field was: 47 (54.0%) from Pediatrics/Endocrinology, 13 (14.9%) from Biology/Genetics, 12 (13.8%) from Psychology/Psychiatry and 15 (17.2%) from Surgical Professions. All trainees were asked to complete an evaluation form on the last day of the TS to gain feedback on how to improve the next one. A further survey was sent at the end of 2017 to provide information about the overall long-term impact of the TSs. Seventy-eight (89.7%) trainees completed evaluation forms at the end of the respective TSs. Replies to the subsequent survey were received from 76 (87.4%) of trainees. A total of 72/76 (94.7%) responders reported that they continue to be active in the field of DSD. The vast majority (64/68, 94.1%) reported that the TSs had enlarged their professional networks. Among the 76 respondent trainees, 11.8% (n = 9) had applied for a research grant and 10.5% (n = 8) had received a fellowship related to DSD since their TS attendance., Conclusions: According to our results, the majority of TS participants continue to be active in the field of DSD and have enlarged their professional networks following participation at the TS. These findings indicate the need of this type of educational program and justify ongoing efforts to provide postgraduate multidisciplinary training in rare diseases such as DSD.

Background: Disorders of sex development (DSD) have an estimated frequency of 0.5% of live births encompassing a variety of urogenital anomalies ranging from mild hypospadias to a discrepancy between sex chromosomes and external genitalia. In order to identify the underlying genetic etiology, we had performed exome sequencing in a subset of DSD cases with 46,XY karyotype and were able to identify the causative genetic variant in 35% of cases. While the genetic etiology was not ascertained in more than half of the cases, a large number of variants of unknown clinical significance (VUS) were identified in those exomes., Methods: To investigate the relevance of these VUS in regards to the patient's phenotype, we utilized a mouse model in which the presence of a Y chromosome from the poschiavinus strain (Y POS ) on a C57BL/6J (B6) background results in XY undervirilization and sex reversal, a phenotype characteristic to a large subset of human 46,XY DSD cases. We assessed gene expression differences between B6-Y B6 and undervirilized B6-Y POS gonads at E11.5 and identified 515 differentially expressed genes (308 underexpressed and 207 overexpressed in B6-Y POS males)., Results: We identified 15 novel candidate genes potentially involved in 46,XY DSD pathogenesis by filtering the list of human VUS-carrying genes provided by exome sequencing with the list of differentially expressed genes from B6-Y POS mouse model. Additionally, we identified that 7 of the 15 candidate genes were significantly underexpressed in the XY gonads of mice with suppressed Sox9 expression in Sertoli cells suggesting that some of the candidate genes may be downstream of a well-known sex determining gene, Sox9., Conclusion: The use of a DSD-specific animal model improves variant interpretation by correlating human sequence variants with transcriptome variation.

Background: Cytoplasmic sex allocation distorters, which arise from cytonuclear conflict over the optimal investment into male versus female reproductive function, are some of the best-researched examples for genomic conflict. Among hermaphrodites, many such distorters have been found in plants, while, to our knowledge, none have been clearly documented in animals., Methods: Here we provide a quantitative test for cytonuclear conflict over sex allocation in the simultaneously hermaphroditic flatworm Macrostomum lignano. We used a quantitative genetic breeding design, employing pair-wise crosses of 2 × 15 independent inbred lines, to partition the phenotypic variance in several traits (including sex allocation) into its nuclear and cytoplasmic components., Results: Although the nuclear genetic background had a significant effect on all traits analyzed, we found significant cytoplasmic genetic variation only for ovary size, there explaining just 4.1% of the variance. A subsequent statistical power analysis showed that the experimental design had considerable power to detect cytonuclear interactions., Conclusion: We conclude that there were no strong effects of cytonuclear conflict in the studied populations, possibly because the usually compact mitochondrial genomes in animals have a lower evolvability than the large mitochondrial genomes in plants or because the sampled populations currently do not harbor variation at putative distorter and/or the restorer loci.

Background: Inbreeding mating has been widely accepted as the key mechanism to enhance homozygosity which normally will decrease the fitness of the population. Although this result has been validated by a large amount of biological data from the natural populations, a mathematical proof of these experimental discoveries is still not complete. A related question is whether we can extend the well-established result regarding the mean fitness from a randomly mating population to inbreeding populations. A confirmative answer may provide insights into the frequent occurrence of self-fertilization populations., Results: This work presents a theoretic proof of the result that, for a large inbreeding population with directional relative genotype fitness, the mean fitness of population increases monotonically. However, it cannot be extended to the case with over-dominant genotype fitness. In addition, by employing multiplicative intersection hypothesis, we prove that inbreeding mating does decrease the mean fitness of polygenic population in general, but does not decrease the mean fitness with mixed dominant-recessive genotypes. We also prove a novel result that inbreeding depression depends on not only the mating pattern but also genetic structure of population., Conclusions: For natural inbreeding populations without serious inbreeding depression, our theoretical analysis suggests the majority of its genotypes should be additive or dominant-recessive genotypes. This result gives a reason to explain why many hermaphroditism populations do not show severe inbreeding depression. In addition, the calculated purging rate shows that inbreeding mating purges the deleterious mutants more efficiently than randomly mating does.

NR5A1 is the key regulator of adrenal and gonadal development in both humans and mice. Recently, a missense substitution in human NR5A1 , p.R92W, was shown to underlie gonadal dysgenesis in genetic males and testicular formation in genetic females. Here, we investigated the phenotypic effects of the p.R92W mutation on murine development. Mice carrying the p.R92W mutation manifested a similar but milder phenotype than that of the previously described Nr5a1 knockout mice. Importantly, mutation-positive XX mice showed no signs of masculinization. These results, together with prior observations, indicate that the p.R92W mutation in NR5A1/Nr5a1 encodes unique molecules that disrupt male gonadal development in both humans and mice and induces testicular formation specifically in human females. Our findings provide novel insights into the conservation and divergence in the molecular networks underlying mammalian sexual development.