Congenital absence of the vas deferens: Cystic fibrosis transmembrane regulatory gene mutations.

Congenital absence of the vas deferens (CAVD) is a rare genetic condition first discovered in the mid-18th century related to mutations in the cystic fibrosis transmembrane regulatory genes. The condition is typically found during work-up of male infertility, and the majority of cases can be diagnosed with complete history and physical examination and pertinent investigations. The condition can be separated into three subcategories, and genetic advances have led to a much better understanding behind the disease, its pathogenesis, and options for treatment. In this review, we discuss the genetics, pathogenesis, embryology, and diagnosis of treatment of CAVD. Future work in this area likely will aim to better understand the epigenetic factors that influence the development of the condition in order to identify potential upstream therapeutic targets.

Uterovaginal Anomalies: A Guide for the Generalist Obstetrician-Gynecologist.

Congenital gynecologic anomalies result from interruption of embryologic development of the female reproductive tract. The anomalies may be hymenal, vaginal, cervical, or uterine. The impact of these anomalies is variable: some are asymptomatic, incidental findings that require no intervention, others require simple surgical management, while some complex anomalies may require a multidisciplinary approach with extensive surgical expertise for optimal outcomes. Uterovaginal anomalies may occur in isolation or in association with other malformations, such as renal anomalies. The origin, presentation, evaluation and treatment of these conditions are reviewed here.

A Practical Approach to Congenital Urogenital Anomalies in Female Pediatric Patients.

Congenital anomalies of the female reproductive tract are relatively common and can be both confusing to understand as well as challenging to diagnose and manage in a busy pediatric clinical practice. Here, we lay out some of the most common genitourinary tract anomalies in female pediatric patients. We highlight the key embryologic development, present case examples, and discuss appropriate testing, treatment, and counseling for patients and their families regarding congenital disorders of the vulva, vagina, uterus, ovaries, and associated pathology. The goal of this review is to demystify these conditions and provide a practical guide for the general pediatrician who is often at the frontline making the initial diagnosis and caring for these patients. [Pediatr Ann. 2020;49(4):e188-e195.].

The embryology of persistent cloaca and urogenital sinus malformations.

Cloacal malformations are characterized by the confluence of the lower urinary tract, the female reproductive tract, and the rectum to create a common channel with a single opening on the perineum. The presence of a cloaca is a normal phase of early human embryological development. Between the 4th and 7th weeks of gestation, the cloaca undergoes subdivision to form the hindgut and urogenital sinus. Failure of this process results in the congenital anomaly termed persistent cloaca (PC). The term urorectal septum malformation sequence (URSMS) is also used to describe this anomaly. The classic description of this process which is still cited in many standard textbooks dates from the 19th century. However, this has been increasingly called into question by the findings of studies using modern scientific methodology. Urogenital sinus anomalies are defined by the confluence of the urethra and vagina to form a common channel of varying length with a single perineal opening. In this condition, the anorectal canal opens separately on the perineum. The presence of a urogenital sinus represents a transient phase of the normal development of the lower genital tract in the female fetus. However, the form of urogenital sinus most commonly encountered in the developed world is a feature of disordered sexual differentiation and does not arise simply from the persistence of the anatomical structure which is a feature of normal fetal development.

The embryology of persistent cloaca and urogenital sinus malformations / 亚洲男科学杂志(英文版)

Cloacal malformations are characterized by the confluence of the lower urinary tract, the female reproductive tract, and the rectum to create a common channel with a single opening on the perineum. The presence of a cloaca is a normal phase of early human embryological development. Between the 4th and 7th weeks of gestation, the cloaca undergoes subdivision to form the hindgut and urogenital sinus. Failure of this process results in the congenital anomaly termed persistent cloaca (PC). The term urorectal septum malformation sequence (URSMS) is also used to describe this anomaly. The classic description of this process which is still cited in many standard textbooks dates from the 19th century. However, this has been increasingly called into question by the findings of studies using modern scientific methodology. Urogenital sinus anomalies are defined by the confluence of the urethra and vagina to form a common channel of varying length with a single perineal opening. In this condition, the anorectal canal opens separately on the perineum. The presence of a urogenital sinus represents a transient phase of the normal development of the lower genital tract in the female fetus. However, the form of urogenital sinus most commonly encountered in the developed world is a feature of disordered sexual differentiation and does not arise simply from the persistence of the anatomical structure which is a feature of normal fetal development.

Interkinetic nuclear movements promote apical expansion in pseudostratified epithelia at the expense of apicobasal elongation.

Pseudostratified epithelia (PSE) are a common type of columnar epithelia found in a wealth of embryonic and adult tissues such as ectodermal placodes, the trachea, the ureter, the gut and the neuroepithelium. PSE are characterized by the choreographed displacement of cells' nuclei along the apicobasal axis according to phases of their cell cycle. Such movements, called interkinetic movements (INM), have been proposed to influence tissue expansion and shape and suggested as culprit in several congenital diseases such as CAKUT (Congenital anomalies of kidney and urinary tract) and esophageal atresia. INM rely on cytoskeleton dynamics just as adhesion, contractility and mitosis do. Therefore, long term impairment of INM without affecting proliferation and adhesion is currently technically unachievable. Here we bypassed this hurdle by generating a 2D agent-based model of a proliferating PSE and compared its output to the growth of the chick neuroepithelium to assess the interplay between INM and these other important cell processes during growth of a PSE. We found that INM directly generates apical expansion and apical nuclear crowding. In addition, our data strongly suggest that apicobasal elongation of cells is not an emerging property of a proliferative PSE but rather requires a specific elongation program. We then discuss how such program might functionally link INM, tissue growth and differentiation.

Applicability of Magnetic Resonance Imaging in the Assessment of Fetal Urinary Tract Malformations.

OBJECTIVE: To assess the applicability of magnetic resonance imaging (MRI) to complement ultrasound in the diagnosis of fetal urinary tract anomalies. METHODS: This was a retrospective cohort study that included 41 women between 19 weeks and 37 weeks and 6 days of gestation carrying fetuses with malformations of the urinary tract which were initially diagnosed by ultrasound and then referred for MRI. In all cases, the diagnosis was confirmed after birth either through imaging or autopsy. A surface coil was positioned over the abdomen and T2-weighted sequences were obtained in the axial, coronal, and sagittal planes; T1 in at least one plane; and three-dimensional (3-D) TRUFI in fetuses with dilatation of the urinary tract. RESULTS: Mean gestational age at the time of MRI examination was 28.21 weeks. The rapid T2 sequences allowed all the anomalies of the fetal urinary tract to be assessed, whereas 3-D TRUFI sequencing proved very useful in evaluating anomalies involving dilatation of the urinary tract. The signs of pulmonary hypoplasia characterized by hypointense signal in the T2-weighted sequences were identified in 13 of the 41 fetuses. CONCLUSION: MRI confirmed and added information to the ultrasound regarding fetal urinary tract anomalies, as well as information related to the other associated malformations, their progress in the prenatal period, and possible postnatal prognosis.

Impact of next generation sequencing on our understanding of CAKUT.

Congenital abnormalities of the kidney and urinary tract (CAKUT) form the leading cause of pediatric end-stage renal disease. Knowledge on the molecular mechanisms that underlie CAKUT leads to the improvement of DNA diagnostics and counseling regarding prognosis and recurrence risk estimation for CAKUT patients and their relatives. Implementation of next generation sequencing in research and diagnostic settings has led to the identification of the molecular basis of many developmental diseases. In this review, we summarize the efforts on next generation sequencing in CAKUT research and we discuss how next generation sequencing added to our understanding of CAKUT genetics. Although next generation sequencing has certainly proven to be a game changer in the field of disease gene identification and novel CAKUT-causing gene variants have been identified, most CAKUT cases still remain unsolved. Occurring with genetic and phenotypic heterogeneity along with incomplete penetrance, the identification of CAKUT etiology poses many challenges. We see great potential for combined -omics approaches that include next generation sequencing in the identification of CAKUT-specific biomarkers, which is necessary to optimize the care for CAKUT patients.

Anhydramnios in the Setting of Renal Malformations: The National Institutes of Health Workshop Summary.

Anhydramnios in the setting of severe malformations of the fetal kidney and urinary tract is associated with a high incidence of stillbirths and life-threatening complications, including severe pulmonary hypoplasia, umbilical cord compression, and perinatal asphyxia. To prevent such adverse outcomes, some centers in the United States and elsewhere are offering amniotic fluid restoration for women diagnosed with anhydramnios in the setting of fetal renal malformations. The procedures include infusions of amniotic fluid substitutes (normal saline), percutaneously or through an amnioport-an implanted system for serial or continuous infusion of normal saline to maintain the desired amniotic fluid volume. The procedures are intended to prevent pulmonary hypoplasia and allow the pregnancy to progress closer to term gestation, enabling postnatal renal management, including long-term dialysis and renal transplantation. However, these procedures have not been recommended as standard of care by the professional societies because there are many knowledge gaps, including few data on short-term and long-term renal outcomes. The available diagnostic methods do not provide reliable prognostic information, and the current maternal and fetal interventions have not been standardized. To address these unresolved issues and to propose a research agenda, the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Diabetes and Digestive and Kidney Diseases invited a panel of experts to a workshop in August 2016. This report provides a summary of that meeting.

Potential Interference of Oil Vehicles on Genital Tubercle Development during the Fetal Period in ICR Mice.

Corn oil, sesame oil, and 10% ethanol in corn oil are commonly used as dosing vehicles in toxicology studies. Since these vegetable oils contain bioactive compounds, it is important for toxicology studies to characterize the toxicities of the dosing vehicles themselves. It has been recently proposed that the width of the genital tubercle (GT), the dorsal-ventral length (D-V length) of the GT, and urethral tube closure in mouse fetuses can be used as novel markers for monitoring sexual development in mice. However, how these parameters are influenced by the dosing vehicles themselves remains unclear. Therefore, we evaluated the effects of corn oil, sesame oil, and 10% ethanol in corn oil on GT width, D-V length, and GT morphology in ICR mice. Our results showed that all three vehicles influenced GT width and D-V length, but not GT morphology, suggesting that the effects of dosing vehicles themselves might need to be considered when GT width or D-V length is used as a parameter to evaluate the effects of chemicals on GT development.

Prenatal diagnosis of urinary tract anomalies, a cohort study in the Northern Netherlands.

OBJECTIVE: To describe prevalence, time of diagnosis, and type of birth in children and fetuses with urinary tract (UT) anomalies after the introduction of the anomaly scan in the Netherlands in 2007. METHODS: We selected, from a population-based congenital anomaly registry, children and fetuses with UT anomalies born between 2008 and 2014. Cases were defined according to type of UT anomaly and whether isolated or with associated anomalies. Information was collected on time of diagnosis and type of birth. RESULTS: We included 487 cases. Total prevalence increased from 34.0 in 2008 to 42.3 per 10 000 births in 2014, mainly by an increase in anomalies of the collecting system. Almost 70% presented as isolated. Anomalies of the renal parenchyma were more often associated with genetic or other anomalies (47.3%) than anomalies of the collecting system (19.0%). The proportion of prenatally diagnosed cases increased from 59.3% in 2008 to 80.9% in 2014. Termination of pregnancy occurred in 14.8%, of which the majority were UT anomalies associated with a genetic disorder or other anomalies. CONCLUSION: In the period after the introduction of the anomaly scan, we observed an increasing prevalence of anomalies of the collecting system, but no increase in termination of pregnancies.

HNF1B controls epithelial organization and cell polarity during ureteric bud branching and collecting duct morphogenesis.

Kidney development depends crucially on proper ureteric bud branching giving rise to the entire collecting duct system. The transcription factor HNF1B is required for the early steps of ureteric bud branching, yet the molecular and cellular events regulated by HNF1B are poorly understood. We report that specific removal of Hnf1b from the ureteric bud leads to defective cell-cell contacts and apicobasal polarity during the early branching events. High-resolution ex vivo imaging combined with a membranous fluorescent reporter strategy show decreased mutant cell rearrangements during mitosis-associated cell dispersal and severe epithelial disorganization. Molecular analysis reveals downregulation of Gdnf-Ret pathway components and suggests that HNF1B acts both upstream and downstream of Ret signaling by directly regulating Gfra1 and Etv5 Subsequently, Hnf1b deletion leads to massively mispatterned ureteric tree network, defective collecting duct differentiation and disrupted tissue architecture, which leads to cystogenesis. Consistently, mRNA-seq analysis shows that the most impacted genes encode intrinsic cell-membrane components with transporter activity. Our study uncovers a fundamental and recurring role of HNF1B in epithelial organization during early ureteric bud branching and in further patterning and differentiation of the collecting duct system in mouse.

Assessing the impact of in-utero exposures: potential effects of paracetamol on male reproductive development.

Human male reproductive disorders (cryptorchidism, hypospadias, testicular cancer and low sperm counts) are common and some may be increasing in incidence worldwide. These associated disorders can arise from subnormal testosterone production during fetal life. This has resulted in a focus on in-utero environmental influences that may result in reproductive effects on the offspring in later life. Over recent years, there has been a dramatic increase in the scientific literature describing associations between in-utero environmental exposures (eg, industrial chemicals and pharmaceuticals) and subsequent reproductive outcomes in male offspring. This includes studies investigating a potential role for in-utero analgesic exposure(s) on the fetal testis; however, providing definitive evidence of such effects presents numerous challenges. In this review, we describe an approach to assessing the potential clinical relevance of in-utero (and postnatal) environmental exposures on subsequent male reproductive function using exposure to the analgesic paracetamol as an example.

High prevalence of same-sex twins in patients with cloacal exstrophy: Support for embryological association with monozygotic twinning.

PURPOSE: Previous studies have hypothesized that cloacal exstrophy may be caused by errors early in embryological development related to monozygotic twinning. This study reports the prevalence of twins in a large cohort of patients with cloacal exstrophy. METHODS: Patients with cloacal exstrophy treated 1974-2015 were reviewed for reports of multiple gestation or conjoined twinning. The genetic sex of the patient and their twin, and any mention of anomaly in the twin were recorded. Neither placental exam nor genetic testing results were available to definitively determine zygosity. RESULTS: Of 71 patients, 10 had a live born twin (14%), all of whom were of the same genetic sex as the affected patient. One additional patient's twin suffered intrauterine fetal demise, and another patient had a conjoined heteropagus twin. None of the twins were affected by exstrophy-epispadias complex. The rate of twin birth in this cohort was 4.4-7.7 higher than that reported by the Centers for Disease Control in the general population time period (P<0.001), with a striking preponderance of same-sex pairs. CONCLUSIONS: The highly significant prevalence of same-sex twin pairs within this cohort supports the hypothesis that the embryogenesis of cloacal exstrophy may be related to errors in monozygotic twinning. LEVEL OF EVIDENCE: 2b.

Fetal Serum ß2-Microglobulin and Postnatal Renal Function in Lower Urinary Tract Obstruction Treated with Vesicoamniotic Shunt.

INTRODUCTION: Although mortality has decreased for fetuses with lower urinary tract obstruction treated with vesicoamniotic shunt (VAS) placement, survivors remain at risk for long-term renal impairment. We tested the association of fetal serum ß2-microglobulin (fsß2M) with postnatal renal function in these patients, hypothesizing that fsß2M may predict such renal impairment. MATERIALS AND METHODS: fsß2M was obtained in patients undergoing VAS placement. The primary outcome was renal function at 3-12 months of life, as assessed by a pediatric nephrologist using medical records. Patients were divided into two groups: (1) 'stable renal function' - probable stable long-term renal function and reasonable growth - and (2) 'loss of renal function' - early loss of renal function and failure to thrive. RESULTS: Nineteen patients with preoperative fsß2M received a VAS. Of the 14 survivors, those with fsß2M ≤5.6 mg/l tended to have stable renal function compared to those with fsß2M >5.6 mg/l [5/6 (83.3%) vs. 2/8 (25.0%), OR = 15.00, 95% CI 0.70-709.89; p = 0.1026]. Eight of 9 patients followed for >12 months of age had outcomes consistent with the initial renal assessments. DISCUSSION: Patients with initial fsß2M >5.6 mg/l and treated with VAS tended to have poor renal outcomes.

Why do undescended testes and posterior urethral valve occur together?

BACKGROUND/AIM: Undescended testis (UDT) occurs in ~2 % of newborn males, and occasionally these infants also have posterior urethral valve (PUV). The cause of this relationship is uncertain. We aimed to review the literature to identify publications documenting co-occurrence of UDT and PUV, and to summarise the theories of co-occurrence. METHODS: A search of the literature (Embase, Medline, Pubmed; 1947-2015) was undertaken to identify publications describing the link between UDT in PUV patients, as well as PUV in UDT patients. Ten publications in English were found with both UDT and PUV: 9 articles describing the frequency of UDT in patients with PUV, and 1 article examining the frequency of PUV in infants with UDT. RESULTS: UDT occurred in 12-17 % of PUV compared with 1-2 % in the control population, consistent with a 10-fold increase. PUV occurred in 1.2 % of UDT patients compared with 0.01 % in the control population, consistent with a 100-fold increase. DISCUSSION: PUV leads to a 10-fold increase in occurrence of UDT, while the presence of UDT causes a 100-fold increase in occurrence of PUV. Four main theories of causation have been proposed, each of which have some merit but little supporting evidence, leaving the cause of simultaneous occurrence of PUV and UDT uncertain.

Clarification of mammalian cloacal morphogenesis using high-resolution episcopic microscopy.

The developmental process through which the cloaca transforms from one hollow structure to two separated urinary and digestive outlets remains controversial and speculative. Here, we use high-resolution episcopic microscopy to examine a comprehensive series of normal and mutant mouse cloaca in which the detailed 3-dimensional (3-D) morphological features are illuminated throughout the development. We provide evidence that the dorsal peri-cloacal mesenchyme (dPCM) remains stationary while other surrounding tissues grow towards it. This causes dramatic changes of spatial relationship among caudal structures and morphological transformation of the cloaca. The 3-D characterizations of Dkk1 mutants reveal a hyperplastic defect of dPCM, which leads to a significant anterior shift of the caudal boundary of the cloaca, premature occlusion of the cloaca and, imperforate anus phenotype. Conversely, Shh knockout causes a severe hypoplastic defect of cloaca mesenchyme including dPCM and persistent cloaca. Collectively, these findings suggest that formation of the dPCM is critical for cloacal morphogenesis and furthermore, growth and movement of the mesenchymal tissues towards the dPCM lead to the cloaca occlusion and separation of the urinary and digestive outlets.

Persistent Urogenital Sinus: Diagnostic Imaging for Clinical Management. What Does the Radiologist Need to Know?

BACKGROUND: Persistent urogenital sinus (PUGS) is a congenital pathological condition characterized by an abnormal communication between the urethra and vagina. It may be a part of a complex syndrome and can be more often associated with congenital malformations affecting the genitourinary tract system (33%) such as intersex, rectovaginal communication, bladder agenesis, absence of vagina, and hydrocolpos. The correct radiological assessment of PUGS is especially useful for clinicians since the exact anatomical evaluation of this abnormality is a crucial factor for surgical planning. The imaging study modalities, which are essentially based on ultrasonography, voiding cystourethrography, and magnetic resonance imaging, could be misinterpreted if not correctly performed. AIM: The aim of this article is to highlight this rare pathological condition and to help general radiologists in achieving the correct technical approach for the diagnosis. Special attention will be paid in discussing the role of different imaging modalities and their contribution to the diagnosis and clinical management of patients.