Sexual Development最新文献

Introduction: Needlefish (Belonidae family) comprises 44 known species distributed worldwide. These species are predominantly marine but include estuarine representatives and 12 freshwater species. Among the recognized species, 8 are endemic to South American rivers. Cytogenetic studies of Belonidae are scarce and mostly limited to describing the diploid chromosome number (2n) and karyotypic structure.

Methods: We used classical and molecular cytogenetic markers to karyotypically characterize Pseudotylosurus microps to understand the evolutionary processes of Belonidae species in the Amazon basin.

Results: P. microps exhibited different diploid numbers between males (2n = 47, 3m + 3sm + 41st/a FN = 53) and females (2n = 48, 4m + 4sm + 40st/a FN = 56). Our study revealed the first case of multiple sex chromosomes in the Belonidae family.

Conclusion: These findings describe a multiple sex chromosome system of the type X1X1X2X2/X1X2Y. The C-banding pattern and 5S rDNA mapping suggest that this system likely resulted from a tandem fusion between a homolog of pair 1 and a homolog of pair 3, producing a large acrocentric Y chromosome. We propose that karyotypic changes due to internal chromosomal rearrangements, as observed in P. microps, can lead to species diversification and, in some cases, the emergence of a heteromorphic and multiple sex chromosome system.

Introduction: Hydrocolpos, a rare condition characterized by cystic dilatation of the vagina, can arise from various etiologies, including isolated imperforate hymen and vaginal atresia. Genetic conditions, such as Bardet-Biedl syndrome (BBS), may also manifest with hydrocolpos as part of urogenital malformations.

Methods: We present a case of neonatal hydrocolpos associated with BBS. Sequencing of 19 BBS genes was performed to elucidate the genetic basis of the syndrome.

Results: Genetic analysis revealed a novel frameshift indel variant (c.1543_1546dup p.Thr516Argfs*7) in the BBS10 gene. This finding expands the spectrum of BBS mutations and underscores the importance of genetic evaluation in patients with hydrocolpos, particularly when associated with additional clinical features suggestive of syndromic etiology.

Conclusion: Pediatric urologists should maintain a high index of suspicion for underlying genetic conditions, including BBS, in neonates presenting with hydrocolpos, given the potential for more severe associated complications such as renal and retinal diseases, obesity, and polydactyly.

Background: Canine cryptorchidism, manifested by an abnormal testicular position, poses significant health risks and reproductive challenges in affected males. Despite a high prevalence, estimated at up to 10% in the canine population, a comprehensive understanding of its pathogenesis remains elusive. Studies in human cryptorchids and knockout mice have identified key factors involved in testicular descent, including INSL3, RXFP2, and AR. To date, only three DNA variants, found in the RXFP2, HMGA2, and KAT6A genes, have been associated with canine cryptorchidism.

Summary: This review briefly summarizes current knowledge on testicular descent and the factors that regulate this process, based on cryptorchidism in humans and mice. It also highlights recent findings related to canine cryptorchidism, focusing on the INSL3, HMGA2, and KAT6A genes. The most significant results are discussed, with an emphasis on the role of the epididymis in testicular descent. This report presents insights that may facilitate further research aiming to broaden our understanding of canine cryptorchidism pathogenesis.

Key messages: DNA polymorphism in the KAT6A gene, associated with changes in global H3K9 acetylation, as well as the DNA methylation pattern in the INSL3 gene, suggest that further research should strongly focus on epigenetic modifications. In addition, the development of the epididymo-testicular junction and the link between cryptorchidism prevalence and dog size should be further investigated.

Introduction: Recent studies have demonstrated that the production of bidirectional enhancer-derived transcripts (eRNAs) is a characteristic of an active cis-regulatory element (CRE). Higher levels of eRNAs synthesis correlate with the activation of histone modifications, a potentially valuable tool for deciphering the complexity of the gene regulatory network.

Method: To understand the changes of CREs during gonadal development in mice, we collected gonadal WT1-positive cells from the piggyBac-Wt1-mCherry-2A-EGFP (PBWt1-RG) reporter strain at E13.5, E16.5, and P0 in both sexes and conducted cap analysis of gene expression (CAGE) analysis, which is capable to capture transcription start sites (TSSs). We compared the levels of intergenic bidirectional RNAs, i.e., potentially eRNAs, according to sex at each stage (testis somatic cells vs. ovary somatic cells at E13.5, E16.5, and P0) and stage in each sex (E13.5 vs. E16.5, E16.5 vs. P0, and E13.5 vs. P0 in testis somatic cells or ovary somatic cells). Intergenic RNAs with significant changes (|Log2FC| > 1, p < 0.05) were selected.

Results: The TSS profile of intergenic RNAs changed more profoundly in testis somatic cells than in ovary somatic cells, suggesting that embryonic testicular development is driven by larger changes in the transcriptional regulatory network than ovarian development. Based on the profiles of the predicted transcription factors (TFs) that would bind to the active CREs during gonadal development, the NR4A, EGR, and TCF3 families would be novel TFs to play pivotal roles in gonadal development.

Conclusion: Identifying active CREs using eRNAs would provide a means to comprehensively understand the transcriptional regulatory system, leading to valuable insights into the gonadal development of male and female individuals.

Introduction: The presence of Y-chromosomal material in females with Turner syndrome (TS) is a well-established risk factor for developing gonadoblastoma and malignant transformations thereof. However, these events are rarely seen in TS patients with no Y-chromosomal material. Thus, it is the current understanding that parts of the Y-chromosome are essential for the malignant transformation of gonadoblastoma in the dysgenetic gonad.

Methods: We report a case of a TS female with an apparent 46,X,idic(Xq) karyotype, who was diagnosed with a metastatic dysgerminoma. Whole exome sequencing of the tumor and blood, along with RNA sequencing of the tumor, was performed to comprehensively search for cryptic Y-chromosomal material and pathogenic variants.

Results: No Y-chromosomal material was detected in either tumor or blood. Whole exome-sequencing of DNA and RNA revealed a pathogenic somatic gain-of-function mutation in KIT and a pathogenic missense mutation in MTOR. The patient underwent total hysterectomy with bilateral salpingo-oophorectomy, followed by adjuvant chemotherapy. Unfortunately, she died due to chemotherapy-induced pneumonitis 7 months after the initial diagnosis.

Conclusion: Females with TS can develop metastatic dysgerminoma even in the absence of Y-chromosomal material. This questions the current understanding of Y-chromosomal material being essential for the malignant transformation of a gonadoblastoma in the dysgenetic gonad.

Background: Our multidisciplinary team (MDT) is a large specialized team based in Semarang, Indonesia, that cares for a wide variety of pediatric and adult individuals with differences of sex development (DSD) from across Indonesia. Here, we describe our work over the last 17 years.

Methods: We analyzed phenotypic, hormonal, and genetic findings from clinical records for all patients referred to our MDT during the period 2004-2020.

Results: Among 1,184 DSD patients, 10% had sex chromosome DSD, 67% had 46,XY DSD, and 23% had 46,XX DSD. The most common sex chromosome anomaly was Turner syndrome (45,X) (55 cases). For patients with 46,XY DSD under-masculinization was the most common diagnosis (311 cases), and for 46,XX DSD, a defect of Müllerian development was most common (131 cases) followed by congenital adrenal hyperplasia (CAH) (116 cases). Sanger sequencing, MLPA, and targeted gene sequencing of 257 patients with 46,XY DSD found likely causative variants in 21% (55 cases), with 13 diagnostic genes implicated. The most affected gene codes for the androgen receptor. Molecular analysis identified a diagnosis for 69 of 116 patients with CAH, with 62 carrying variants in CYP21A2 including four novel variants, and 7 patients carrying variants in CYP11B1. In many cases, these genetic diagnoses influenced the clinical management of patients and their families.

Conclusions: Our work has highlighted the occurrence of different DSDs in Indonesia. By applying sequencing technologies as part of our clinical care, we have delivered a number of genetic diagnoses and identified novel pathogenic variants in some genes, which may be clinically specific to Indonesia. Genetics can inform many aspects of DSD clinical management, and while many of our patients remain undiagnosed, we hope that future testing may provide answers for even more.

Introduction: The pathogenic variants in DEAH-box RNA helicase DHX37 are one of the major causes of 46,XY gonadal dysgenesis and testicular regression syndrome (TRS). To date, only 13 different missense variants have been reported. We report two additional cases with different clinical presentations carrying two novel variants in the DHX37 gene.

Case presentation and results: Case 1 (4.4-year-old boy) presented with significant micropenis and cryptorchidism and was diagnosed as TRS. Case 2 (13.5-year-old girl) had a 46,XY karyotype with female external genitalia and was diagnosed as GD. Two novel DHX37 variants affecting the RecA2 domain, p.G478R and p.L627F, were identified in these cases. Both variants identified in the probands were also present in their unaffected mother.

Conclusion: Our findings broaden the variant spectrum of DHX37 in 46,XY differences of sex development (DSD) individuals.

Abstracts of the 11th I-DSD Symposium.