Normal Reproductive function in male mice lacking pituitary kisspeptin receptor.

The anterior pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) regulate gonadal development, gametogenesis and the secretion of the gonadal steroid hormones. The gonadotroph is primarily regulated by hypothalamic secretion of gonadotropin-releasing hormone (GnRH) from neurons of the rostral hypothalamus and is mediated by GnRH receptor signaling. Kisspeptin (KISS1)/kisspeptin receptor (KISS1R) signaling in GnRH neurons plays an essential role in reproductive function. As the kisspeptin receptor is present in the pituitary, kisspeptin signaling via the Kiss1r may regulate reproductive function at the level of pituitary. Using Cre/Lox technology, we deleted the Kiss1r gene in pituitary gonadotropes (PKiRKO). PKiRKO male and females have normal genital development, puberty onset, and fertility. Females have normal LH, FSH and estradiol while males had significantly increased basal serum FSH levels with no differences in basal serum LH, or testosterone levels. Overall, these findings indicate that the pituitary KISS1R does not play a role in male reproduction.

Medico-legal evidence collection in child sexual assault cases: a forensic significance

Background Every year, millions of children face sexual exploitation worldwide. In India, 109 children (National Crime Records Bureau2018) were sexually abused everyday (22% jump from the previous year). Even with advanced DNA techniques, the conviction rate remains low. The methods used for forensic DNA evidence analysis vary around the world, but the primary step of biological evidence collection plays the most vital role. Proper and timely evidence collection from the victim by a trained medical professional is important. Main body Dynamics of child sexual assault being massively different from an adult rape demands altogether different approach of evidence collection. A standard sexual kit employed for evidence collection needs urgent modifications considering genital development of pre- and post-pubertal victims. In the present study, parameters including systemic collection and evaluation of forensic evidences, medico-legal examination, and developmental consequences of sexual assault on pre-pubertal victims were assessed. Further suggestions for separate evidence collection kit during medico-legal examination were given for pre-pubertal victims and alleged accused in sexual assault cases in order to streamline and for better evaluation of DNA analysis in forensic laboratories. Conclusion The importance of expert medical practitioners plays a significant role in collection of appropriate information and evidences from the victim of sexual assault. General guidelines for evidence collection in sexual assault cases are not well suited for pre-pubertal victims. Appropriate reforms pertaining to the age and genital development of victims are required. Securing clothing as forensic evidence is essential in most cases as it turned out to be the exclusive evidence bearing material. The purpose of this article is to bring awareness about the thorough medical examination and modified sexual assault kit for pre-pubertal victims and alleged accused for a better approach in evidence collection and conviction rate.

Expanding DSD Phenotypes Associated with Variants in the DEAH-Box RNA Helicase DHX37

Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS). DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy. In a cohort of 140 individuals with 46,XY DSD, we identified 7 children with either 46,XY complete gonadal dysgenesis or 46,XY TRS carrying rare or novel DHX37 variants. A novel p.R390H variant within the RecA1 domain was identified in a girl with complete gonadal dysgenesis. A paternally inherited p.R487H variant, previously associated with a recessive congenital developmental syndrome, was carried by a boy with a syndromic form of 46,XY DSD. His phenotype may be explained in part by a novel homozygous loss-of-function variant in the <i>NGLY1</i> gene, which causes a congenital disorder of deglycosylation. Remarkably, a homozygous p.T477H variant was identified in a boy with TRS. His fertile father had unilateral testicular regression with typical male genital development. This expands the DSD phenotypes associated with DHX37. Structural analysis of all variants predicted deleterious effects on helicase function. Similar to all other known ribosomopathies, the mechanism of pathogenesis is unknown.

Ultrasound Diagnosis of Abnormalities in the Development of the Uterus and Vagina with Impaired Menstrual Blood Flow in Girls

The objective: to study and analyze the indicators of the diagnostic informativeness of the echographic study of anomalies in the development of the uterus and vagina with impaired outflow of menstrual blood in girls. Materials and methods. For the study, a group of 37 patients (n=37), from 10 to 19 years old, was selected, who were divided into 2 subgroups: 1 subgroup – patients with doubling of the uterus and vagina without disturbing the outflow of menstrual blood (n=25), 2 subgroup – patients with doubling uterus and vagina with partial aplasia of one vagina (n=12). Most of the subjects – 26 girls (10,3 %) – applied for a referral to clarify the diagnosis, 11 (29,7 %) – without complaints from the genitals for differential diagnosis. Results. At vaginoscopy at all patients the mucous membrane of pink color with well expressed folding. According to ultrasound of the pelvic organs in 1 subgroup in 17 patients the vagina was divided into 2 parts full, and in 8 – incomplete septum, two uteruses were located, parallel to each other, the contours were smooth, clear, M-echo was determined in both uteruses, two cervix with cervical canals. In subgroup 2, 9 patients showed protrusion of different sizes of one of the walls of the vagina, 2 patients in the lateral, 1 – in the upper lateral zone of the vagina was determined by a punctate hole with an inflammatory roller – fistulous entrance to the second vagina. In all patients from the side of the aplasia of the vagina, the uterine cavity is expanded from 10 to 25 mm, filled with echonegative contents. The reliability of the results of ultrasound scanning of anomalies of genital development is equal: the sensitivity of the method – 84,0 %, specificity – 90,9 %, accuracy – 89,1 %. Conclusions. Manifestation of malformations of the genitals with impaired outflow of menstrual blood occurs at puberty, as after menarche above the aplastic segment of the genital tract accumulates menstrual blood and tumor formation, accompanied by characteristic clinical manifestations. Diagnosis of this pathology is quite complex, which can lead to errors in determining the nature of the pathological condition and, as a consequence, unwarranted surgery. Thus, the need to further improve the methods of diagnosis and management of patients with doubling of the uterus and vagina with impaired menstrual blood flow remains relevant, which will identify diseases at an earlier age or immediately after the appearance of complaints and symptoms.

Novel variants in the stem cell niche factor WNT2B define the disease phenotype as a congenital enteropathy with ocular dysgenesis

WNT2B is a member of the Wnt family, a group of signal transduction proteins involved in embryologic development and stem cell renewal and maintenance. We recently reported homozygous nonsense variants in WNT2B in three individuals with severe, neonatal-onset diarrhea, and intestinal failure. Here we present a fourth case, from a separate family, with neonatal diarrhea associated with novel compound heterozygous WNT2B variants. One of the two variants was a frameshift variant (c.423del [p.Phe141fs]), while the other was a missense change (c.722 G > A [p.G241D]) that we predict through homology modeling to be deleterious, disrupting post-translational acylation. This patient presented as a neonate with severe diet-induced (osmotic) diarrhea and growth failure resulting in dependence on parenteral nutrition. Her gastrointestinal histology revealed abnormal cellular architecture particularly in the stomach and colon, including oxyntic atrophy, abnormal distribution of enteroendocrine cells, and a paucity of colonic crypt glands. In addition to her gastrointestinal findings, she had bilateral corneal clouding and atypical genital development later identified as a testicular 46,XX difference/disorder of sexual development. Upon review of the previously reported cases, two others also had anterior segment ocular anomalies though none had atypical genital development. This growing case series suggests that variants in WNT2B are associated with an oculo-intestinal (and possibly gonadal) syndrome, due to the protein’s putative involvement in multiple developmental and stem cell maintenance pathways.

Rapidly Progressing Early Puberty in a Boy with Bilateral Basal Ganglia Germinoma and TREX1 Variant

Introduction: Organic lesions, including brain tumors, should be suspected in boys with precocious puberty. However, it is not usually suspected in children with early puberty. Case Presentation: Here we present an extremely rare case of rapidly progressing early puberty with basal ganglia germinoma coupled with three-prime repair exonuclease 1 (TREX1) variant. This was a 10-year-old-boy with borderline mental retardation and rapidly progressing puberty. Physical examination revealed 10 mL testes (Tanner stage 3 for genital development), and his bone age was that of a 12-year old boy. Laboratory findings showed abnormally elevated serum β-human chorionic gonadotropin (23.0 mIU/mL; reference, 0-10 mIU/mL), and suppressed LH level (

Unraveling the Genetic Basis for the Rapid Diversification of Male Genitalia between Drosophila Species

In the last 240,000 years, males of the Drosophila simulans species clade have evolved striking differences in the morphology of their epandrial posterior lobes and claspers (surstyli). These appendages are used for grasping the female during mating and so their divergence is most likely driven by sexual selection. Mapping studies indicate a highly polygenic and generally additive genetic basis for these morphological differences. However, we have limited understanding of the gene regulatory networks that control the development of genital structures and how they evolved to result in this rapid phenotypic diversification. Here, we used new D. simulans/D. mauritiana introgression lines on chromosome arm 3L to generate higher resolution maps of posterior lobe and clasper differences between these species. We then carried out RNA-seq on the developing genitalia of both species to identify the expressed genes and those that are differentially expressed between the two species. This allowed us to test the function of expressed positional candidates during genital development in D. melanogaster. We identified several new genes involved in the development and possibly the evolution of these genital structures, including the transcription factors Hairy and Grunge. Furthermore, we discovered that during clasper development Hairy negatively regulates tartan (trn), a gene known to contribute to divergence in clasper morphology. Taken together, our results provide new insights into the regulation of genital development and how this has evolved between species.

Unravelling the genetic basis for the rapid diversification of male genitalia between Drosophila species

In the last 240,000 years, males of the Drosophila simulans species clade have evolved striking differences in the morphology of their epandrial posterior lobes and claspers (surstyli). These changes have most likely been driven by sexual selection and mapping studies indicate a highly polygenic and generally additive genetic basis. However, we have limited understanding of the gene regulatory networks that control the development of genital structures and how they evolved to result in this rapid phenotypic diversification. Here, we used new D. simulans / D. mauritiana introgression lines on chromosome 3L to generate higher resolution maps of posterior lobe and clasper differences between these species. We then carried out RNA-seq on the developing genitalia of both species to identify the genes expressed during this process and those that are differentially expressed between the two species. This allowed us to test the function of expressed positional candidates during genital development in D. melanogaster. We identified several new genes involved in the development and possibly the evolution of these genital structures, including the transcription factors Hairy and Grunge. Furthermore, we discovered that during clasper development Hairy negatively regulates tartan, a gene known to contribute to divergence in clasper morphology. Taken together our results provide new insights into the regulation of genital development and how this evolves between species.