Immunoexpression Pattern of Autophagy-Related Proteins in Human Congenital Anomalies of the Kidney and Urinary Tract.

The purpose of this study was to evaluate the spatiotemporal immunoexpression pattern of microtubule-associated protein 1 light chain 3 beta (LC3B), glucose-regulated protein 78 (GRP78), heat shock protein 70 (HSP70), and lysosomal-associated membrane protein 2A (LAMP2A) in normal human fetal kidney development (CTRL) and kidneys affected with congenital anomalies of the kidney and urinary tract (CAKUT). Human fetal kidneys (control, horseshoe, dysplastic, duplex, and hypoplastic) from the 18th to the 38th developmental week underwent epifluorescence microscopy analysis after being stained with antibodies. Immunoreactivity was quantified in various kidney structures, and expression dynamics were examined using linear and nonlinear regression modeling. The punctate expression of LC3B was observed mainly in tubules and glomerular cells, with dysplastic kidneys displaying distinct staining patterns. In the control group's glomeruli, LAMP2A showed a sporadic, punctate signal; in contrast to other phenotypes, duplex kidneys showed significantly stronger expression in convoluted tubules. GRP78 had a weaker expression in CAKUT kidneys, especially hypoplastic ones, while normal kidneys exhibited punctate staining of convoluted tubules and glomeruli. HSP70 staining varied among phenotypes, with dysplastic and hypoplastic kidneys exhibiting stronger staining compared to controls. Expression dynamics varied among observed autophagy markers and phenotypes, indicating their potential roles in normal and dysfunctional kidney development.

Expression of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) Candidate Genes EDA2R, PCDH9, and TRAF7 in Normal Human Kidney Development and CAKUT.

Approximately half of the cases of chronic kidney disease (CKD) in childhood are caused by congenital anomalies of the kidney and urinary tract (CAKUT). Specific genes were identified as having significant importance in regard to the underlying genetic factors responsible for the CAKUT phenotype, and in our research, we focused on analyzing and comparing the expression levels of ectodysplasin A2 receptor (EDA2R), protocadherin9 (PCDH9), and TNF receptor-associated factor 7 (TRAF7) proteins in the cortex and medulla of healthy control kidneys during developmental phases 2, 3, and 4. We also performed an analysis of the area percentages of the mentioned proteins in the cortical and medullary sections of healthy embryonic and fetal kidneys compared to those affected by CAKUT, including duplex kidneys (DK), horseshoe kidneys (HK), hypoplastic kidneys (HYP), and dysplastic kidneys (DYS). We found that the CAKUT candidate gene proteins EDA2R, PCDH9, and TRAF7 are all expressed during normal human kidney development stages. In DYS, the expression of EDA2R was higher than in normal kidneys, likely due to EDA2R's role in apoptosis, which was upregulated in specific cases and could possibly contribute to the formation of DYS. The expression of PCDH9 was lower in HK, which can be attributed to the possible role of PCDH9 in cell migration suppression. Decreased PCDH9 expression is linked to increased cell migration, potentially contributing to the development of HK. The level of TRAF7 expression was reduced in all examined kidney disorders compared to normal kidneys, suggesting that this reduction might be attributed to the crucial role of TRAF7 in the formation of endothelium and ciliogenesis, both of which are essential for normal kidney development. Further research is required to ascertain the function of these proteins in both the typical development of the kidney and in CAKUT.

Gestational diabetes mellitus induces congenital anomalies of the kidney and urinary tract in mice by altering RET/MAPK/ERK pathway.

Gestational diabetes mellitus (GDM) presents a substantial population health concern. Previous studies have revealed that GDM can ultimately influence nephron endowment. In this study, we established a GDM mouse model to investigate the embryological alterations and molecular mechanisms underlying the development of congenital anomalies of the kidney and urinary tract (CAKUT) affected by GDM. Our study highlights that GDM could contribute to the manifestation of CAKUT, with prevalent phenotypes characterized by isolated hydronephrosis and duplex kidney complicated with hydronephrosis in mice. Ectopic ureteric buds (UBs) and extended length of common nephric ducts (CNDs) were noted in the metanephric development stage. The expression of Ret and downstream p-ERK activity were enhanced in UBs, which indicated the alteration of RET/MAPK/ERK pathway may be one of the mechanisms contributing to the increased occurrence of CAKUT associated with GDM.

GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are prevalent birth defects. Although pathogenic CAKUT genes are known, they are insufficient to reveal the causes for all patients. Our previous studies indicated GEN1 as a pathogenic gene of CAKUT in mice, and this study further investigated the correlation between GEN1 and human CAKUT. METHODS: In this study, DNA from 910 individuals with CAKUT was collected; 26 GEN1 rare variants were identified, and two GEN1 (missense) variants in a non-CAKUT group were found. Mainly due to the stability results of the predicted mutant on the website, in vitro, 10 variants (eight CAKUT, two non-CAKUT) were selected to verify mutant protein stability. In addition, mainly based on the division of the mutation site located in the functional region of the GEN1 protein, 8 variants (six CAKUT, two non-CAKUT) were selected to verify enzymatic hydrolysis, and the splice variant GEN1 (c.1071 + 3(IVS10) A > G) was selected to verify shear ability. Based on the results of in vitro experiments and higher frequency, three sites with the most significant functional change were selected to build mouse models. RESULTS: Protein stability changed in six variants in the CAKUT group. Based on electrophoretic mobility shift assay of eight variants (six CAKUT, two non-CAKUT), the enzymatic hydrolysis and DNA-binding abilities of mutant proteins were impaired in the CAKUT group. The most serious functional damage was observed in the Gen1 variant that produced a truncated protein. A mini-gene splicing assay showed that the variant GEN1 (c.1071 + 3(IVS10) A > G) in the CAKUT group significantly affected splicing function. An abnormal exon10 was detected in the mini-gene splicing assay. Point-mutant mouse strains were constructed (Gen1: c.1068 + 3 A > G, p.R400X, and p.T105R) based on the variant frequency in the CAKUT group and functional impairment in vitro study and CAKUT phenotypes were replicated in each. CONCLUSION: Overall, our findings indicated GEN1 as a risk factor for human CAKUT.

Expansion of the core features of VACTERL association to include genital anomalies.

Genital anomalies have been reported with VACTERL association but not considered a core feature. Acute and chronic complications stemming from unrecognized genital anomalies have been reported in adolescents and young adults with VACTERL association. We sought to determine the frequency and severity of genital anomalies in VACTERL patients and identify which core features were more frequently associated with genital anomalies. A retrospective chart review from January 2010 to October 2021 identified 211 patients with two or more core VACTERL features, 34% of whom had a genital anomaly. The majority of genital anomalies (83% of those in males and 90% in females) were classified as functionally significant (requiring surgical intervention or causing functional impairment). The frequency of genital anomalies in the VACTERL cohort was higher if anorectal malformations or renal anomalies were present in both males and females and if vertebral anomalies were present in females. Due to their functional significance, genital anomalies should be assessed in all patients with two or more core features of VACTERL association, especially in those with anorectal or renal anomalies. Most genital anomalies in males will be detected on physical examination but additional investigation is often needed to detect genital anomalies in females. The timing and type of investigation are subjects for future study.

LUMBAR syndrome-OEIS complex overlap: A case series and review.

We present three new and six published infants with overlapping features of LUMBAR syndrome (lower body hemangioma, urogenital anomalies, spinal cord malformations, bony deformities, anorectal/arterial anomalies and renal anomalies) and OEIS complex (omphalocele, exstrophy, imperforate anus, and spinal defects), also known as cloacal exstrophy. OEIS is included under the recently proposed umbrella coined recurrent constellations of embryonic malformations (RCEMs). The RCEMs represent a phenotypically overlapping spectrum of rare disorders of caudal dysgenesis with unknown cause but likely shared pathogenesis. It has recently been proposed that LUMBAR be considered an RCEM. This report of infants with combined features of OEIS and LUMBAR is the first to demonstrate an overlap between LUMBAR and another RCEM, which supports LUMBAR's inclusion within the RCEM spectrum.

Congenital anomalies of kidney and urinary tract (CAKUT) and associated extra-renal anomalies in fetal autopsies.

OBJECTIVES AND BACKGROUND: According to studies, 1% of all pregnancies have an abnormality, with 20-30% of those affecting the genitourinary system. Congenital abnormalities of the kidney and urinary tract (CAKUT) is one of the primary causes of perinatal and neonatal mortality in children. Many extra-renal congenital illnesses accompany these defects, affecting the patient's prognosis. This study aims to determine the subtypes, frequency, and extra-renal defects associated with congenital anomalies of the urinary system, which is the major cause of mortality in fetal and infant autopsies throughout the perinatal and neonatal eras. We believe that our study will contribute to the literature because few autopsy investigations can give this data. MATERIALS AND METHODS: The study included 110 fetal autopsies between January 1997 and May 2019. 10% were newborns under the age of one year, and 90% were fetus autopsies. RESULTS: Males accounted for 67.3% of the cases, while females accounted for 35 (31.8%) (the gender of one case could not be determined). Renal dysplasia was the most frequent CAKUT, with a rate of 22.73%, followed by renal agenesis, with a rate of 20.0%. Eighty-four cases (76.3%) showed disease in at least one other organ system. Musculoskeletal system (MSS) abnormalities were the most common associated system anomaly, with one or more MSS anomalies (34.55%) detected in 38 cases. CONCLUSION: Finally, we want to underline that CAKUT and its associated anomalies are not uncommon. Prenatal imaging, genetic investigation, and/or postmortem examination should all be used to screen for CAKUT. This information is helpful for the mother's future pregnancy management and parental genetic counseling.

Exome sequencing in individuals with congenital anomalies of the kidney and urinary tract (CAKUT): a single-center experience.

Individuals with congenital anomalies of the kidney and urinary tract (CAKUT) show a broad spectrum of malformations. CAKUT can occur in an isolated fashion or as part of a syndromic disorder and can lead to end-stage kidney failure. A monogenic cause can be identified in ~12% of affected individuals. This study investigated a single-center CAKUT cohort analyzed by exome sequencing (ES). Emphasis was placed on the question whether diagnostic yield differs between certain CAKUT phenotypes (e.g., bilateral kidney affection, unilateral kidney affection or only urinary tract affection). 86 unrelated individuals with CAKUT were categorized according to their phenotype and analyzed by ES to identify a monogenic cause. Prioritized variants were rated according to the recommendations of the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science. Diagnostic yields of different phenotypic categories were compared. Clinical data were collected using a standardized questionnaire. In the study cohort, 7/86 individuals had a (likely) pathogenic variant in the genes PAX2, PBX1, EYA1, or SALL1. Additionally, in one individual, a 17q12 deletion syndrome (including HNF1B) was detected. 64 individuals had a kidney affection, which was bilateral in 36. All solved cases (8/86, 9%) had bilateral kidney affection (diagnostic yield in subcohort: 8/36, 22%). Although the diagnostic yield in CAKUT cohorts is low, our single-center experience argues, that, in individuals with bilateral kidney affection, monogenic burden is higher than in those with unilateral kidney or only urinary tract affection.

Anatomy and embryology of congenital surgical anomalies: Congenital Anomalies of the Kidney and Urinary Tract.

Congenital anomalies of the kidney and urinary tract or "CAKUT" describes a spectrum of developmental disorders with a range of associated clinical presentations and functional consequences. CAKUT underlies the majority of chronic kidney disease and kidney replacement therapy requirement in children, but functional deterioration can also emerge in adulthood. Understanding the normal embryological processes involved in kidney development allows us to appreciate the timing and sequence of critical events implicated when things go wrong. In this review, we will describe the normal developmental mechanisms and relate this to what we currently know about the pathological processes involved in various forms of CAKUT. We will also review the proposed etiological factors, in particular genetics, involved in CAKUT.

Disease mechanisms of monogenic congenital anomalies of the kidney and urinary tract American Journal of Medical Genetics Part C.

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is a developmental disorder of the kidney and/or genito-urinary tract that results in end stage kidney disease (ESKD) in up to 50% of children. Despite the congenital nature of the disease, CAKUT accounts for almost 10% of adult onset ESKD. Multiple lines of evidence suggest that CAKUT is a Mendelian disorder, including the observation of familial clustering of CAKUT. Pathogenesis in CAKUT is embryonic in origin, with disturbances of kidney and urinary tract development resulting in a heterogeneous range of disease phenotypes. Despite polygenic and environmental factors being implicated, a significant proportion of CAKUT is monogenic in origin, with studies demonstrating single gene defects in 10%-20% of patients with CAKUT. Here, we review monogenic disease causation with emphasis on the etiological role of gene developmental pathways in CAKUT.

Accurate identification and surgical correction of type IIb uterine malformation using synchronized hysteroscopy and laparoscopy.

OBJECTIVE: To introduce an effective approach for accurate identification and treatment of type IIb uterine malformation using synchronized hysteroscopy and laparoscopy. DESIGN: Step-by-step video explanation of the surgical procedure with still pictures and surgical video clips to demonstrate the detailed technique. The patient provided written informed consent for video and data collection for research purposes. The study was approved by the local ethics committee of Shengjing Hospital of China Medical University. SETTING: Academic medical center. PATIENT(S): A 32-year-old young woman diagnosed with a right unicornuate uterus with a left rudimentary horn, with a 2-year history of dysmenorrhea. INTERVENTION(S): First, the patient was diagnosed with a unicornuate uterus with a rudimentary horn using ultrasonography and magnetic resonance imaging before the surgery. During surgery, synchronized hysteroscopy and laparoscopy coupled with a light test was performed to make a definite identification of the type IIb uterine malformation. During treatment of the type IIb uterine malformation, there were two key steps: resected the rudimentary horn and reserved more myometrial tissue to reduce the risk of uterine rupture in a subsequent pregnancy; and corrected the uterus to prevent future uterine prolapse. For the suture technique, suturing during resection was performed instead of suturing after complete resection to reduce the intraoperative bleeding as much as possible. Furthermore, tubal catheterization and hydrotubation under hysteroscopy monitoring were performed. MAIN OUTCOME MEASURE(S): Value and feasibility of synchronized hysteroscopic and laparoscopic identification and treatment of the type IIb uterine malformation. RESULT(S): The total operation time was 89 minutes. The postoperative pathological findings revealed that the endometrium was found in the rudimentary horn. No dysmenorrhea was found during follow-up. At 26 months after the operation, the patient became pregnant naturally. Cesarean section was performed at 36 weeks + 2 days owing to premature rupture of the membranes. CONCLUSION(S): For the accurate identification and management of a type IIb uterine malformation, synchronized hysteroscopy and laparoscopy is an effective and feasible method.

Aqueous vaginal contrast and scheduled hematocolpos with magnetic resonance imaging to delineate complex müllerian anomalies.

OBJECTIVE: To demonstrate the advantage of using aqueous vaginal contrast and scheduled hematocolpos with magnetic resonance imaging (MRI) to improve the delineation of gynecologic anatomy and to recommend that this modality be considered in patients with complex müllerian anomalies. DESIGN: Video demonstration of MRI adjuncts to improve visualization of gynecologic anatomy. SETTING: Academic Hospital. PATIENT(S): A patient with obstructed hemivagina and ipsilateral renal agenesis (OHVIRA) who presented for definitive surgical management. INTERVENTION(S): OHVIRA is a unilateral obstructed müllerian anomaly that presents typically after menarche with progressively worsening dysmenorrhea caused by progressive distension of the obstructed hemivagina and uterine horn. The definitive treatment for this anomaly is resection of the unilateral obstruction. When the obstructed hemivagina is within close proximity to the patent hemivagina, vaginal septum resection should be performed to relieve the obstruction successfully. However, when the obstructed hemivagina and uterine horn are not adjacent to the patent hemivagina, a simple septum resection is not feasible and there is a high rate of restenosis if anastomosis is attempted. In this case, laparoscopic removal of the obstructed uterine horn, fallopian tube, cervix, and vagina should be considered as an alternative approach to resolving the obstruction. A surgical approach can be recommended only once the surgeon has a clear understanding of the patient's pelvic anatomy and the magnitude of the obstruction. In the presented case, a 17-year-old patient with OHVIRA presented for definitive surgical management. While on hormonal suppression, a pelvic MRI was performed that identified a uterus didelphys with a left hemiuterus and cervix communicating with a patent vagina. The right hemiuterus and cervix were measured 2.5 cm from the patent vagina. However, because of hormonal suppression, the vaginal cavity was decompressed, making it very difficult to discern the relationship between the two uteri and vaginas. To better determine whether vaginal septum resection to relieve the obstruction was feasible, norethindrone was discontinued to allow menstrual blood to fill the obstructed hemivagina followed by a subsequent pelvic MRI with aqueous vaginal contrast to fill the patent vagina with contrast gel to improve the visualization of the decompressed vaginal cavities. MAIN OUTCOME MEASURE(S): Advantage of aqueous vaginal contrast and scheduled hematocolpos with MRI to image pelvic anatomy in a patient with a complex müllerian anomaly to guide surgical decision-making. RESULT(S): The addition of vaginal aqueous contrast clearly delineated the course and caliber of the patent vagina and its relationship to the obstructed hemivagina, now filled with blood. The inferior margin was in closer proximity to the patent vagina, but with only a very narrow segment (<1 cm) adjacent to the patent vagina and the obstructed cervix was displaced superiorly, now measuring 3.5 cm above the patent vagina. Surgical management options were discussed with the patient, and given the superior location of the obstructed uterus and cervix with only a narrow border of the vagina in continuity with the patent vagina, the risk of postoperative stenosis after vaginal septum resection was determined to be too high. The decision was made to proceed with a laparoscopic resection of the obstructed right side, and the patient underwent laparoscopic resection of the right hemiuterus, fallopian tube, cervix, and vagina. Intraoperatively, a survey of the pelvis again confirmed that the two vaginas were too far to reconnect safely without a high risk of stenosis. The patient recovered without complications postoperatively and her menses resumed without any pain. CONCLUSION(S): We highlight the use of two techniques to optimize MRI imaging of pelvic anatomy in a patient with a complex müllerian anomaly. First, the use of aqueous vaginal contrast with MRI is advantageous to clearly delineate the course and caliber of the patent vagina in patients with complex gynecologic anatomy. Second, cessation of hormonal suppression to allow menstruation to cause hematocolpos helped delineate the relationship between the obstructed vagina and patent vagina. In the presented case, these MRI adjuncts provided necessary detail that could not be appreciated with standard MRI to confirm that vaginal septum resection to preserve the right uterus would be too high a risk for postoperative stenosis in this patient. Aqueous vaginal contrast and scheduled hematocolpos should be considered as adjuncts to MRI when standard imaging modalities are unable to clearly describe the relationship between pelvic structures in cases of complex müllerian anomalies to help guide treatment recommendations.

Robotic-assisted laparoscopic cervicouterine anastomosis in a patient with agenesis of the uterine isthmus.

OBJECTIVE: To demonstrate the surgical management of agenesis of the uterine isthmus. DESIGN: Stepwise description of robotic-assisted laparoscopic cervicouterine anastomosis. SETTING: Academic medical center. PATIENT(S): A 27-year-old nulligravida with primary amenorrhea and cyclic pelvic pain. INTERVENTION(S): The patient underwent a robot-assisted cervicouterine anastomosis using the following surgical steps: adhesiolysis of the right ovary from the rudimentary uterine horn; vesicouterine peritoneal fold dissection and mobilization of the cervical canal; the opening of the cervical canal and dilatation with Hegar dilators; longitudinal incision of the lower third of the anterior uterine wall up to the endometrial cavity; insertion of a 14 Ch Foley catheter, not inflated, fixed to the cervix with a suture and removed after 7 days; and closure of the cervicouterine breach with a double-layer Vicryl suture. Informed consent was obtained from the patient for the use of video and images. MAIN OUTCOME MEASURE(S): After 3 months, the patency of the anastomosis site was assessed via hysteroscopy. Subsequent follow-up was performed by referring physicians. RESULT(S): Postoperatively, anatomic continuity was restored and the patient was menstruating with regular monthly cycles; furthermore, cyclic pelvic pain was relieved. Few cases of this condition have been reported in the literature and, currently, surgical treatment of agenesis of the uterine isthmus is controversial, with some treatments including laparoscopic-assisted uterocervical anastomosis using a stent to prevent restenosis, primary cervicouterine anastomosis by laparotomy performed with a Foley catheter in the cervical canal, and anastomosis of the uterine isthmus agenesis. However, to our knowledge, we are the first to use a robotic approach. Preservation of reproductive function and symptom relief represent the goals of the surgery. Therefore, hysterectomy cannot be considered as a treatment option. However, after a cervicouterine anastomosis procedure, the normal uterine morphology cannot be achieved; cyclic abdominal pain may remain after surgical treatment. In this case, an alternative surgical approach, such as hysterectomy, can be considered. CONCLUSION(S): Robotic-assisted treatment of this uncommon müllerian anomaly is feasible and may be an alternative to hysterectomy in individuals who wish to preserve fertility. Follow-up is needed to evaluate fertility and reproductive function.

Expanding the KIF4A-associated phenotype.

Kinesin super family (KIF) genes encode motor kinesins, a family of evolutionary conserved proteins, involved in intracellular trafficking of various cargoes. These proteins are critical for various physiological processes including neuron function and survival, ciliary function and ciliogenesis, and cell-cycle progression. Recent evidence suggests that alterations in motor kinesin genes can lead to a variety of human diseases, including monogenic disorders. Neuropathies, impaired higher brain functions, structural brain abnormalities and multiple congenital anomalies (i.e., renal, urogenital, and limb anomalies) can result from pathogenic variants in many KIF genes. We expand the phenotype associated with KIF4A variants from developmental delay and intellectual disability with or without epilepsy to a congenital anomaly phenotype with hydrocephalus and various brain anomalies at the more severe end of phenotypic manifestations. Additional anomalies of the kidneys and urinary tract, congenital lymphedema, eye, and dental anomalies seem to be variably associated and overlap with clinical signs observed in other kinesinopathies. Caution still applies to missense variants, but hopefully, future work will further establish genotype-phenotype correlations in a larger number of patients and functional studies may give further insights into the complex function of KIF4A.

Homozygous WNT9B variants in two families with bilateral renal agenesis/hypoplasia/dysplasia.

WNT9B plays a key role in the development of the mammalian urogenital system. It is essential for the induction of mesonephric and metanephric tubules, the regulation of renal tubule morphogenesis, and the regulation of renal progenitor cell expansion and differentiation. To our knowledge, WNT9B has not been associated with renal defects in humans; however, WNT9B-/- mice have renal agenesis/hypoplasia and reproductive tract abnormalities. We report four individuals from two unrelated consanguineous families with bilateral renal agenesis/hypoplasia/dysplasia and homozygous variants in WNT9B. The proband from Family 1 has bilateral renal cystic dysplasia and chronic kidney disease. He has two deceased siblings who presented with bilateral renal hypoplasia/agenesis. The three affected family members were homozygous for a missense variant in WNT9B (NM_003396.2: c.949G>A/p.(Gly317Arg)). The proband from Family 2 has renal hypoplasia/dysplasia, chronic kidney disease, and is homozygous for a nonsense variant in WNT9B (NM_003396.2: c.11dupC/p.(Pro5Alafs*52)). Two of her siblings died in the neonatal period, one confirmed to be in the context of oligohydramnios. The proband's unaffected brother is also homozygous for the nonsense variant in WNT9B, suggesting nonpenetrance. We propose a novel association of WNT9B and renal anomalies in humans. Further study is needed to delineate the contribution of WNT9B to genitourinary anomalies in humans.

New mutation in WT1 gene in a boy with an incomplete form of Denys-Drash syndrome: A CARE-compliant case report.

RATIONALE: Pediatric patients with WTl-associated syndromes (including Wilms' tumor-aniridia syndrome and Denys-Drash syndrome), Perlman syndrome, mosaic aneuploidy, and Fanconi anemia with a biallelic breast cancer type 2 susceptibility protein mutation have the highest risk of developing Wilms' tumor. PATIENT CONCERNS AND DIAGNOSIS: We describe a patient with bilateral metachronous Wilms' tumor, ambiguous genitalia characterized by 46, XY disorder of sexual development (DSD) with scrotal hypospadias and bilateral abdominal cryptorchidism, but without nephropathy. At the age of 7 months, the child underwent left nephrectomy with left orchiopexy. At follow-up after 8 months, a second tumor with a diameter of 10 mm was detected in abdominal CT scans at the lower pole of the right kidney. INTERVENTION: Intra-operative macroscopic inspection of the right kidney revealed a tight attachment of the right proximal ureter to the tumor. Thus, retroperitoneoscopic resection of the lower pole of the right kidney had to be changed to an open surgical procedure with partial resection of the proximal ureter and high uretero-ureterostomy. We subsequently performed orchiopexy and two-stage correction of hypospadias using a free skin graft. OUTCOMES: At the last follow-up at the age of 8 years, no pathology requiring treatment was noted. A pair-end-reading (2 × 125) DNA analysis with an average coverage of at least 70 to 100 × revealed a previously unknown heterozygous mutation in exon 7 of the Wilms' tumor suppressor gene 1 (WT1) gene (chr11:32417947G>A), leading to the appearance of a site of premature translation termination in codon 369 (p.Arg369Ter, NM_024426.4). This mutation had not been registered previously in the control samples "1000 genomes," Exome Sequencing Project 6500, and the Exome Aggregation Consortium. Thus, to the best of our knowledge this represents a newly identified mutation causing incomplete Denys-Drash syndrome.

A Homozygous Dab1-/- Is a Potential Novel Cause of Autosomal Recessive Congenital Anomalies of the Mice Kidney and Urinary Tract.

This study aimed to explore morphology changes in the kidneys of Dab1-/- (yotari) mice, as well as expression patterns of reelin, NOTCH2, LC3B, and cleaved caspase3 (CASP3) proteins, as potential determinants of normal kidney formation and function. We assumed that Dab1 functional inactivation may cause disorder in a wide spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). Animals were sacrificed at postnatal days P4, P11, and P14. Paraffin-embedded kidney tissues were sectioned and analyzed by immunohistochemistry using specific antibodies. Kidney specimens were examined by bright-field, fluorescence, and electron microscopy. Data were analyzed by two-way ANOVA and t-tests. We noticed that yotari kidneys were smaller in size with a reduced diameter of nephron segments and thinner cortex. TEM microphotographs revealed foot process effacement in the glomeruli (G) of yotari mice, whereas aberrations in the structure of proximal convoluted tubules (PCT) and distal convoluted tubules (DCT) were not observed. A significant increase in reelin expression, NOTCH2, LC3B and cleaved CASP3 proteins was observed in the glomeruli of yotari mice. Renal hypoplasia in conjunction with foot process effacement and elevation in the expression of examined proteins in the glomeruli revealed CAKUT phenotype and loss of functional kidney tissue of yotari.

Uterine synechiae after intrauterine device use: a case series.

PURPOSE: The intrauterine device (IUD) is one of the most effective and safe contraceptive methods. Substantial literature suggests an overall return to normal fertility following IUD removal. However, there are no studies to date that evaluate endometrial function specifically in nulliparous women after levonorgestrel IUD use. METHODS: We present three nulliparous women with a history of levonorgestrel IUD use who were evaluated for uterine dysfunction at the University of California, San Francisco Center for Reproductive Health. These patients had no other known risk factors or history of uterine manipulation, including prior uterine surgery, pelvic radiation, intrauterine infection, hypothalamic amenorrhea, or uterine anomaly. RESULTS: Upon evaluation, these patients were found to have uterine synechiae concerning for Asherman syndrome. All three patients were eventually able to conceive through assisted reproductive technology or natural conception. CONCLUSION: This case series is the first to suggest a possible effect of endometrial dysfunction on fertility resumption following levonorgestrel IUD removal in nulliparous patients. It is possible that a small subset of patients may be at risk for Asherman syndrome after IUD use. Larger prospective trials are needed to explore this possible association.

Bioengineering of the Uterus.

Impairment of uterine structure and function causes infertility, pregnancy loss, and perinatal complications in humans. Some types of uterine impairments such as Asherman's syndrome, also known as uterine synechiae, can be treated medically and surgically in a standard clinical setting, but absolute defects of uterine function or structure cannot be cured by conventional approaches. To overcome such hurdles, partial or whole regeneration and reconstruction of the uterus have recently emerged as new therapeutic strategies. Transplantation of the whole uterus into patients with uterine agenesis results in the successful birth of children. However, it remains an experimental treatment with numerous difficulties such as the need for continuous and long-term use of immunosuppressive drugs until a live birth is achieved. Thus, the generation of the uterus by tissue engineering technologies has become an alternative but indispensable therapeutic strategy to treat patients without a functional or well-structured uterus. For the past 20 years, the bioengineering of the uterus has been studied intensively in animal models, providing the basis for clinical applications. A variety of templates and scaffolds made from natural biomaterials, synthetic materials, or decellularized matrices have been characterized to efficiently generate the uterus in a manner similar to the bioengineering of other organs and tissues. The goal of this review is to provide a comprehensive overview and perspectives of uterine bioengineering focusing on the type, preparation, and characteristics of the currently available scaffolds.