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A region of 160 kb at Xp21.2 has been defined as dosage-sensitive sex reversal (DSS) and includes the NR0B1 gene, considered to be the candidate gene involved in XY gonadal dysgenesis if overexpressed. We describe a girl with 46,XY partial gonadal dysgenesis carrying a 297 kb duplication at Xp21.2 upstream of NR0B1 initially detected by chromosomal microarray analysis. Fine mapping of the breakpoints by whole-genome sequencing showed a tandem duplication of TASL (CXorf21) , GK and partially TAB3 , upstream of NR0B1 . This is the first description of an Xp21.2 duplication upstream of NR0B1 associated with 46,XY partial gonadal dysgenesis.

Introduction: NR5A1 is an essential transcription factor that regulates several target genes involved in reproduction and endocrine function. Pathogenic variants in this gene are responsible for a wide spectrum of disorders/differences of sex development (DSD)., Methods: The molecular study involved Sanger sequencing, in vitro assays, and whole exome sequencing (WES)., Results: Four variants were identified within the NR5A1 non-coding region in 3 patients with 46,XY DSD. In vitro analyses showed that promoter activity was affected in all cases. WES revealed variants in SRA1, WWOX, and WDR11 genes., Discussion/conclusion: Evaluation of clinical and phenotypic significance of variants located in a non-coding region of a gene can be complex, and little is known regarding their association with DSD. Nevertheless, based on the important region for interaction with cofactors essential to promote appropriated sex development and on our in vitro results, it is feasible to say that an impact on gene expression can be expected and that this may be correlated with the DSD pathophysiology presented in our patients. Considering the number of cases that remain elusive after screening for the well-known DSD related genes, we emphasize the importance of a careful molecular analysis of NR5A1 non-coding region which is commonly neglected and might explain some idiopathic DSD cases., (© 2022 S. Karger AG, Basel.)

Introduction: The aim of this retrospective study was to verify the association between the time of diagnosis and initial and final sex assignment in a disorder of sex development (DSD) diagnostic group, looking at the age of the patients at first visit, severity of genital ambiguity, and karyotype., Methods: The time of diagnosis was divided into 3 groups: before 2000, between 2000 and 2006, and after 2006. Data were categorized and analyzed using the χ2 test with α < 0.05., Results: A total of 567 cases were analyzed; 307 were assigned as male, 135 as female, and 125 remained undefined at the first visit. After clinical and laboratory evaluations, 369 patients were male and 198 were female. Neither initial nor final sex assignment proportions changed over time, but there were significant differences in the age at first visit, with referral occurring at an earlier age, as well as more severe genital ambiguity presentations, a higher proportion of sex chromosome aberrations, and a lower frequency of 46,XX DSD cases. This occurred both in the sample as a whole (567 cases) and in the group of 125 patients without definitive sex assignment at the first visit. The results were similar when only 284 patients aged less than 12 months at the first visit were analyzed., Discussion/conclusion: Over time, there were no changes in sex assignment proportions, but there was an increased awareness of the need for early referral and changes in clinical, cytogenetic, and diagnostic aspects., (© 2022 S. Karger AG, Basel.)

Objective: To evaluate, in a sample of patients with disorders of sex development (DSD), data related to the age at referral and their correlation with the initial complaints, gender at referral, defined gender after diagnosis and etiological diagnosis., Methods: Retrospective review of the age at the first consultation and the reason for it, initial social gender and gender after the diagnosis, karyotype and etiological diagnosis of all cases treated at a DSD outpatient clinic between 1989 and 2016. Cases that did not involve DSD and DSD diagnoses that do not usually involve ambiguous genitalia, thus not requiring specialized monitoring, were excluded., Results: Of the 1793 treated cases, 1139 were diagnosed with some type of DSD. This study excluded 430 cases (272 with Turner's syndrome, 66 with Klinefelter syndrome, and 92 with pure gonadal dysgenesis), thus a total 709 individuals were included. Of these, 82.9% were referred due to ambiguous genitalia; only one-quarter were still in the first month of life, and 6.6% were referred due to pubertal delay, with most of them aged 10 years or older. Of these patients, 68.6% had a diagnosis of XY DSD, 22.4% of XX DSD, and 9% of sex chromosome abnormalities., Conclusions: This study presents the largest series in the literature of patients with DSD treated in a single center. The time of referral of the majority of patients with ambiguous genitalia fell short of the ideal, and milder cases of ambiguous genitalia and many with pubertal manifestations were referred even later. The results reinforce the importance of continuing education for professionals who will have the first contact with these patients, mainly pediatricians and neonatologists., (Copyright © 2019 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

In this study, we present 3 cases of Down syndrome (DS) associated with disorders/differences of sex development (DSD) and review the literature on this topic. Case 1: 1-year-old child with male genitalia and DS phenotype, 47,XX,+21 karyotype and testicular DSD. Case 2: 11-month-old child with male genitalia and few DS dysmorphisms, 45,X/47,XY,+21 karyotype, and mixed gonadal dysgenesis. Case 3: 4-month-old child with female genitalia and DS phenotype, 47,XY,+21 karyotype and XY complete gonadal dysgenesis. In the literature, among 188 patients, 107 (57%) had Klinefelter syndrome and 61 (33%) Turner syndrome, 12 (6%) had mixed gonadal dysgenesis, 2 (1%) had partial androgen insensitivity, 2 (1%) ovotesticular DSD, and the others had congenital adrenal hyperplasia, XY partial gonadal dysgenesis, XY complete gonadal dysgenesis, and complete androgen insensitivity (1 case each). A typical DS phenotype was found in all individuals of the revision, with the exception of one case, but DSD features were not always reported. In conclusion, the association of DS with sex chromosome DSD is the most frequently observed, whereas associations with 46,XX and 46,XY DSD is extremely rare., (© 2021 S. Karger AG, Basel.)

Historically, the terms partial (PGD) and mixed gonadal dysgenesis (MGD) have been used to describe incomplete testicular differentiation in individuals with 46,XY or 45,X/46,XY karyotypes, respectively. However, it is currently unclear to what extent clinical features actually differ between these individuals. The aim of this study was to compare clinical, laboratory, and histological findings in these 2 groups. Patients with testicular dysgenesis seen in our service between 1989 and 2013 were selected. Sixty-one patients met the inclusion criteria. Individuals with 46,XY and 45,X/46,XY karyotypes were compared regarding genital features, gonadal histology and function, growth, and associated conditions. Twenty-five had mosaicism with a 45,X cell line (MGD), while a 46,XY karyotype (PGD) was found in 36 cases belonging to 32 families. Mutations in NR5A1, WT1, and SRY genes associated with testicular dysgenesis were found in 12 families. There were no significant differences regarding parental consanguinity, degree of external androgenization, gonadal location, histology, and function, and associated conditions. However, in the MGD group, the presence of a uterus, lower birth weight and length, and short stature were more often observed. Therefore, the use of histological features to classify PDG and MGD should be abandoned and replaced by classification based on karyotype., (© 2019 S. Karger AG, Basel.)

Objective: To describe the case of a male Prader-Willi syndrome (PWS) patient with atypical development features., Description: We report the case of a male adolescent with confirmed diagnosis of PWS which presents atypical phenotype. The patient progressed with spontaneous and complete pubertal development, stature in the normal range, and weight control without any pharmacological treatment, except metformin., Comments: PWS is an imprinting paternally inherited disorder of 15q11-13 characterized by hypotonia in infant age, hyperphagia, varied degrees of mental retardation, behavior problems, hypogonadism, short stature, and other less common findings.