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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]

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. [ABSTRACT FROM AUTHOR]

The human chorionic gonadotropin (hCG) stimulation test that evaluates gonadal steroidogenesis is crucial in the assessment of patients with 46,XY disorders of sex development (DSD). This study aimed to determine a testosterone (T) cutoff level that indicates an adequate testicular function using LC-MS/MS after stimulation with recombinant human chorionic gonadotropin (rhCG) in a single dose. Nineteen prepubertal children with 46,XY DSD and normal T secretion were evaluated. T and dihydrotestosterone (DHT) levels were measured by liquid chromatography technique with tandem mass spectrometry (LC-MS/MS) before and 7 days after rhCG application at 250 µg. We suggest 0.89 ng/mL as the cutoff point for T after rhCG stimulation analyzed by LC-MS/MS. [ABSTRACT FROM AUTHOR]

Youth with intellectual disabilities (IDs) demonstrate below-criteria motor competence (MC) compared with typically developing (TD) youth. Whether differences in MC exist for youth with ID from different countries is unknown. This study examined the MC of youth with ID from Brazil (BR) and the United States (US) and compared it with norms for TD youth as established by the Bruininks–Oseretsky Test of Motor Proficiency (BOT-2). The authors measured 19 BOT-2 test items for bilateral coordination, balance, and upper limb coordination of 502 youth (BR = 252, US = 250) with ID (6–21 years). Raw scores were converted to %ceiling (percentile of highest expected scores). For all test items, no significant differences were seen between BR and US participants in %ceiling scores. Participants from both countries demonstrated equivalent to slightly below BOT-2 norms in 14 of the 19 test items, with lowest scores seen in contralateral synchronizing bilateral coordination, balancing on one leg, and ball handling. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop and cross-validate an equation for estimating percentage body fat (%BF) from body mass index and other potential independent variables among young persons with intellectual disability. Participants were 128 persons with intellectual disability (62 women; age 16–24 years) split between development (n = 98) and cross-validation (n = 30) samples. Dual-energy X-ray absorptiometry served as the reference method for %BF. An equation including 1/body mass index and sex (0 = male; 1 = female) was highly accurate in estimating %BF (p <.001; R2 =.82; standard error of estimate = 5.22%). Mean absolute and root mean square errors were small (3.1% and 3.9%, respectively). A Bland–Altman plot indicated nearly zero mean difference between actual and predicted %BF with modest 95% confidence intervals. The prediction equation was %BF = 56.708 − (729.200 × [1/body mass index]) + (12.134 × sex). Health care professionals may use the prediction equation for monitoring %BF among young people with intellectual disability. [ABSTRACT FROM AUTHOR]

The group of disorders known as 46,XY gonadal dysgenesis (GD) is characterized by anomalies in testis determination, including complete and partial GD (PGD) and testicular regression syndrome (TRS). Several genes are known to be involved in sex development pathways, however approximately 50% of all cases remain elusive. Recent studies have identified variants in DHX37, a gene encoding a putative RNA helicase essential in ribosome biogenesis and previously associated with neurodevelopmental disorders, as a cause of PGD and TRS. To investigate the potential role of DHX37 in disorders of sexual development (DSD), 25 individuals with 46,XY DSD were analyzed and putative pathogenic variants were found in four of them. WES analyses were performed on these patients. In DHX37, the variant p.(Arg308Gln), recurrent associated with DSD, was identified in one patient; the p.(Leu467Val), predicted to be deleterious, was found together with an NR5A1 loss-of-function variant in patient 2; and, the p.(Val999Met) was identified in two unrelated patients, one of whom (patient 3) also carried a pathogenic NR5A1 variant. For both patients carrying DHX37 and NR5A1 pathogenic variants, a digenic inheritance is suggested. Our findings support the importance of DHX37 variants as a cause of disorders of sex development, implying a role in testis development. [ABSTRACT FROM AUTHOR]

Ovotesticular disorders of sex development (OT‐DSD) are characterized by ovarian follicles and seminiferous tubules in the same individual, with a wide range of atypical genitalia. We report on two sibs with atypical genitalia and SRY‐negative 46,XX DSD, OT‐DSD was confirmed only in the boy, while the girl had bilateral ovaries. Chromosome microarray analysis (CMA) showed a 737‐kb duplication at Xq27.1 including the entire SOX3 gene in both sibs, which was confirmed by quantitative real time PCR. Also, X chromosome inactivation assay showed random inactivation in both sibs. Whole exome sequencing revealed no pathogenic or likely pathogenic variant. CMA of the parents showed normal results for both, suggesting that germline mosaicism could be the reason of recurrence of this duplication in the siblings. Our results support a pathogenic role of SOX3 overexpression in 46,XX subjects leading to variable DSD phenotypes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The adipose tissue is an endocrine organ that secretes adipokines such as leptin, which is one of the most important hormones for controlling satiety, metabolism, and energy homeostasis. This hormone acts in the regulation of innate and adaptive immune responses since immune cells have leptin receptors from which this hormone initiates its biological action. These receptors have been identified in hematopoietic stem cells in the bone marrow and mature immune cells, inducing signaling pathways mediated by JAK/STAT, PI3K, and ERK 1/2. It is known that the bone marrow also contains leptin-producing adipocytes, which are crucial for regulating hematopoiesis through largely unknown mechanisms. Therefore, we have reviewed the roles of leptin inside and outside the bone marrow, going beyond its action in the control of satiety. [ABSTRACT FROM AUTHOR]