Materiały źródłowe

• #1 Bladder Exstrophy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK563156/

  Bladder exstrophy is a rare congenital anomaly characterized by a spectrum of anomalies involving the ventral body wall, urinary tract, genitalia, bony pelvis, spine, anus, etc. […] Multiple theories have been put forward for its etiopathogenesis; however, the exact cause still eludes us. […] Although multiple theories highlighting the etiology and pathogenesis of bladder exstrophy have been published, the exact cause still eludes us. Of all these theories, the one by Marshall and Muecke is the most accepted. An abnormally large cloacal membrane causes a wedge effect and prevents the medial migration of the mesenchymal tissue. As a result, the lower abdominal wall is not well-formed. A subsequent rupture of the cloacal membrane results in herniation of all the contents and leading to the clinical picture of bladder-exstrophy-epispadias complex.

• #2 Pathogenesis of bladder exstrophy: A new hypothesis – PubMed

  https://pubmed.ncbi.nlm.nih.gov/26316280/

  Classical bladder exstrophy affects 1 in 30 000 live births. […] Surgical correction in bladder exstrophy would be more effective if the exact pathogenetic mechanism was deduced and the procedure was directed to correct the cause, which is responsible for the defect. […] Thus there is a need to examine pathogenesis of bladder exstrophy. […] The exact embryopathogenesis of bladder exstrophy is unknown. […] Bladder exstrophy epispadias complex (BEEC) is a deformative disruption occurring after embryogenic phase and pubic diastasis, and is central to exstrophy development. […] A working hypothesis can be formulated in line with our observation so that future experiments based this new hypothesis can aim to elucidate the exact pathogenesis.

• #3 The Genomic Architecture of Bladder Exstrophy Epispadias Complex

  https://www.mdpi.com/2073-4425/12/8/1149

  The bladder exstrophy–epispadias complex (BEEC) is an abdominal midline malformation comprising a spectrum of congenital genitourinary abnormalities of the abdominal wall, pelvis, urinary tract, genitalia, anus, and spine. […] The etiology of this malformation is still unknown. Theories have proposed an abnormal overdevelopment of the cloacal membrane preventing medial migration of mesenchyme between the ectodermal and endodermal layers of the lower abdominal wall, resulting in abnormal development of the lower abdominal wall […] or the involvement of cloacal membrane and mesenchymal tissues during their defective embryogenesis. […] The vast majority of BEEC cases are non-syndromic, however, a number of cases have been reported whereby BEEC has also been associated with various other syndromes, malformations, and congenital diseases.

• #4 The Exstrophy-epispadias complex | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-4-23

  Exstrophy-epispadias complex (EEC) results from mechanical disruption or enlargement of the cloacal membrane; the timing of the rupture determines the severity of the malformation. […] The underlying cause remains unknown: both genetic and environmental factors are likely to play a role in the etiology of EEC. […] In 1964 Muecke was the first to report that mechanical disruption or enlargement of the cloacal membrane in chicks prevents the invasion of mesodermal cells along the infraumbilical midline, and thereby results in exstrophy. […] Based on that, Austin et al. provided evidence that in humans, anomalous overgrowth of the cloacal membrane is associated with bladder exstrophy. […] Animal models of EC support the idea that abnormal partitioning of the cloacal membrane causes displacement of the genital tubercle and therefore epispadias formation.

• #5 Exstrophy–Epispadias Complex | 5-Minute Pediatric Consult

  https://peds.unboundmedicine.com/pedscentral/view/5-Minute-Pediatric-Consult/618145/2.1/Exstrophy

  The exstrophyepispadias complex is a rare spectrum of multisystem birth defects involving the genitourinary and gastrointestinal tracts, musculoskeletal system, pelvic floor, and bony pelvis. It is composed of epispadias, bladder exstrophy, and cloacal exstrophy. The latter two conditions present with an open bladder through the anterior abdominal wall. […] Bladder exstrophy: Only known association is related to offspring of in vitro fertilization pregnancies. […] Unclear pathogenesis, but there is an error in embryogenesis. The cloacal membrane may overdevelop and prevent mesenchymal migration, which inhibits formation of normal lower abdominal wall. Without reinforcement, the cloacal membrane ruptures. The timing of this rupture determines the variant of the exstrophyepispadias complex. In bladder exstrophy, rupture of the membrane occurs after the urorectal septum has descended, dividing the genitourinary and gastrointestinal tracts.

• #6 Pathogenesis of Bladder Extrophy

  http://www.fetalultrasound.com/online/text/9-028.HTM

  In the situation of bladder exstrophy, the entire anterior wall of the urinary bladder, the overlying skin, and skeletal muscle are absent. […] Bladder exstrophy has a male predominance of about 3:1. […] Bladder extrophy is not due to developmental arrest during embryogenesis as the human embryo does not pass through any developmental stage that is compatible with either extrophy or epispadias. […] Any interference with the regression of the cloacal membrane will result in extrophy. […] The persistent cloacal membrane acts as a barrier preventing normal midline mesodermal fusion and therefore incomplete closure of the infraumbilical abdominal wall. […] The size and cranial extent of the persistent cloacal membrane at its time of rupture accounts for the severity in the epispadias-extrophy complex.

• #7 Bladder Exstrophy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK563156/

  Several other theories, including the caudal displacement of the genital tubercle, abnormal fluid retention leading to rupture of the embryonic bladder, etc., have been proposed as possible mechanisms in the occurrence of exstrophy bladder. […] Recently, a new hypothesis has been suggested by Varma et al. They have proposed that pubic diastasis is central to the occurrence of exstrophy bladder, and it precedes exstrophy development.

• #8 The Exstrophy-epispadias complex | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-4-23

  Accordingly, on the basis of a developmental study of hereditary anorectal malformations in pig embryos, it has been concluded that agenesis of the dorsal part of the cloacal membrane may form the basis of congenital malformations of cloaca-derived orifices such as hypospadias, epispadias, bladder and cloacal exstrophy, double urethra, and cloacal membrane agenesis. […] Additionally, Thomalla et al. created a hernia defect of the lower abdominal wall of chick embryos by incising the cloacal membrane with a laser. […] The timing of cloacal membrane disruption in this model determined the resulting variant of the EEC, with an earlier disruption (4-6 gestation weeks, before fusion of the urorectal septum to the cloacal membrane) leading to the more severe EC. […] The authors postulated that EEC would form if cloacal membrane rupture occurred just after the urorectal septum completed its descent (6 weeks), but before the initial formation of the genital tubercle.

• #9 Evaluation of the ISL1 gene in the pathogenesis of bladder exstrophy in a Swedish cohort | Human Genome Variation

  https://www.nature.com/articles/hgv20189

  Bladder exstrophy is a congenital closure defect of the urinary bladder with a profound effect on morbidity. […] Although BEEC usually occurs sporadically, studies and case reports have indicated that genetic factors play a role in the pathogenesis of BEEC. […] The recurrence risk of BEEC in offspring or sibs is ~1 in 70100 live births, and the concordance rate in twins is much higher in monozygotic than in dizygotic twins, 45% and 6%, respectively. […] Together, these observations indicate a genetic background behind the congenital malformation, and most likely, several independent genetic factors may contribute. […] Recently, a novel, potentially disease-causing variant in the WNT3 gene was identified. […] A genome-wide association study of 110 classic bladder exstrophy (CBE) patients and 1,177 controls of European origin followed by a meta-analysis identified the rs9291768 variant in genome-wide significant association with isolated CBE.

• #9 Evaluation of the ISL1 gene in the pathogenesis of bladder exstrophy in a Swedish cohort | Human Genome Variation

  https://www.nature.com/articles/hgv20189

  The ISL LIM homeobox 1 (ISL1) on chromosome 5q11.2 is the closest protein-coning gene to the genomic location of rs9291768. […] The association to this region on chromosome 5q11.2 was subsequently replicated in another study of 268 CBE cases from different populations, including 116 DNA samples from Sweden, in which a significant association was identified between CBE and another variant, rs6874700 single-nucleotide polymorphism, located 16kb from rs9291768 in the ISL1 gene locus. […] These two studies suggest ISL1 as a major candidate gene for the development of CBE. […] We did not detect any known or likely pathogenic variants in the ISL1 gene in our cohort. […] One potentially novel missense variant was detected in one patient; however, this variant was inherited from a healthy mother, reducing the pathogenicity score of this variant to that of a variant of unknown significance.

• #9 Evaluation of the ISL1 gene in the pathogenesis of bladder exstrophy in a Swedish cohort | Human Genome Variation

  https://www.nature.com/articles/hgv20189

  We believe that although the c.137CG was inherited from a healthy mother, that does not completely rule out this variant as disease-causing. […] Further support for the involvement of the ISL1 gene in human bladder development was gathered from RNA sequencing in four embryonic and three fetal human bladders collected during weeks 510. […] Our data indicated moderate-to-high ISL1 gene expression in human embryonic and fetal bladder during the period of closing of the abdominal and bladder wall, supporting the importance of the gene in human fetal bladder development. […] In conclusion, we did not detect any known or likely pathogenic variants in the ISL1 gene in 125 Swedish BEEC patients, indicating that variation in the ISL1 gene is not a common genetic mechanism of BEEC development in the Swedish population.

• #10 SPU – Trio Exome Sequencing Implicates Wnt Signaling In The Pathogenesis Of Bladder-Exstrophy-Epispadias Complex

  https://spuonline.org/fallcongress/program/2024/81.cgi

  Bladder-exstrophy-epispadias complex (BEEC) describes a spectrum of lower abdominal and genitourinary midline malformations, including epispadias, bladder exstrophy, and cloacal exstrophy. […] Although the cause of BEEC is uncertain, increased concordance rates among monozygotic (62%) vs. dizygotic twins (11%) and previously identified BEEC candidate genes suggest a hereditary component. […] We identified a de novo pathogenic variant in PORCN (c.1186CT; p.Arg396*) in one proband with bladder exstrophy and focal dermal hypoplasia (FDH). […] PORCN is required for Wnt protein secretion, and variants have previously been described in patients with both bladder exstrophy and FDH. […] In addition, we detected 2 potentially deleterious heterozygous variants in Wnt pathway genes among 2 singlet probands: WNT5A (c.1033GC; p.Asp345His) and WNT8B (c.185GA; p.Arg62His). […] Interestingly, WNT5A knockout mice display severe defects in urethral tube formation. […] This further supports a role of Wnt signaling in disease pathogenesis.

• #11 The Genomic Architecture of Bladder Exstrophy Epispadias Complex

  https://www.mdpi.com/2073-4425/12/8/1149

  The majority of individuals affected by BEEC have no positive family history of BEEC. However, even though familial occurrence is rare, 30 multiplex families have been described. […] The genetic basis of BEEC is consistent with a multifactorial etiology. […] The application of array-based, GWAS, and next generation sequencing techniques in large BEEC cohorts has helped to identify putative disease-causing genes and chromosomal regions in the human genome for both Mendelian and multifactorial BEEC. […] It is reasonable to propose that both inherited and de novo highly penetrant variants could be relevant to the etiology of BEEC as they have been shown for many genetically heterogeneous congenital birth defects such as congenital heart disease. […] New approaches such as gene and pathway enrichment analyses of high-impact de novo variants from whole exome or whole genome data in parent-offspring trios will likely aid in the identification of novel genes and/or pathways to better understand the underlying genetic mechanisms of BEEC, and the potential to use these data to develop therapeutic approaches to help children affected by this devastating congenital disorder.

• #12 Towards a Central Role of ISL1 in the Bladder Exstrophy–Epispadias Complex (BEEC): Computational Characterization of Genetic Variants and Structural Modelling

  https://www.mdpi.com/2073-4425/9/12/609

  Genetic factors play a critical role in the development of human diseases. Recently, several molecular genetic studies have provided multiple lines of evidence for a critical role of genetic factors in the expression of human bladder exstrophy-epispadias complex (BEEC). […] At this point, ISL1 (ISL LIM homeobox 1) has emerged as the major susceptibility gene for classic bladder exstrophy (CBE), in a multifactorial disease model. […] Our analysis suggests that the ISL1 protein specific N-terminal LIM domain (which harbors the variant c.137C > G), limits its transcriptional ability, and might interfere with ISL1-estrogen receptor α interactions. […] In conclusion, our analysis provides further useful insights about the ISL1 gene, which is involved in the formation of the BEEC, and in the development of the urinary bladder.

• #13 EZH2 specifically regulates ISL1 during embryonic urinary tract formation | Scientific Reports

  https://www.nature.com/articles/s41598-024-74303-w

  Isl1 has been described as an embryonic master control gene expressed in the pericloacal mesenchyme. […] Using genome wide association methods, we identified ISL1 as the key susceptibility gene for classic bladder exstrophy (CBE), comprising epispadias and exstrophy of the urinary bladder. […] Our study shows, that Ezh2 is a key regulator of Isl1 during urinary tract formation and suggests tissue specific ISL1 dysregulation as an underlying mechanism for CBE formation. […] Our recent meta-analysis comprised seven independent discovery samples and identified eight genome-wide significant loci, seven of which were novel. […] The regulatory effect of marker rs2303751 was predicted to be much higher than that of the top marker rs6874700 itself. […] EZH2 is well known as the enzymatic catalytic subunit of the PRC2 complex (Polycomb Repressive Complex Subunit 2) and recently it was described to act as a transcription factor.

• #13 EZH2 specifically regulates ISL1 during embryonic urinary tract formation | Scientific Reports

  https://www.nature.com/articles/s41598-024-74303-w

  We demonstrate that EZH2 knockdown in HEK 293 cells and KO in zf larvae downregulates ISL1 expression. […] We think that this tissue specificity is representative for vertebrates, as we find a similar expression in human derived HEK cells. […] Our findings suggest that specific tissue dependent dysregulation of ISL1 might be involved in CBE formation during early urinary bladder development and that this mechanism employs tissue specific regulation of ISL1 through binding of EZH2 on the ISL1 intrinsic Fragment 2.

• #14 SPU – Trio Exome Sequencing Implicates Wnt Signaling In The Pathogenesis Of Bladder-Exstrophy-Epispadias Complex

  https://fallcongress.spuonline.org/program/2024/81.cgi

  Bladder-exstrophy-epispadias complex (BEEC) describes a spectrum of lower abdominal and genitourinary midline malformations, including epispadias, bladder exstrophy, and cloacal exstrophy. […] Although the cause of BEEC is uncertain, increased concordance rates among monozygotic (62%) vs. dizygotic twins (11%) and previously identified BEEC candidate genes suggest a hereditary component. […] We identified a de novo pathogenic variant in PORCN (c.1186CT; p.Arg396*) in one proband with bladder exstrophy and focal dermal hypoplasia (FDH). PORCN is required for Wnt protein secretion, and variants have previously been described in patients with both bladder exstrophy and FDH. […] In addition, we detected 2 potentially deleterious heterozygous variants in Wnt pathway genes among 2 singlet probands: WNT5A (c.1033GC; p.Asp345His) and WNT8B (c.185GA; p.Arg62His).

• #14 SPU – Trio Exome Sequencing Implicates Wnt Signaling In The Pathogenesis Of Bladder-Exstrophy-Epispadias Complex

  https://fallcongress.spuonline.org/program/2024/81.cgi

  Interestingly, WNT5A knockout mice display severe defects in urethral tube formation. […] Through exome analysis, we identified a pathogenic PORCN variant in one proband with bladder exstrophy and FDH, along with 3 potentially deleterious variants in Wnt pathway genes among 3 probands with BEEC. This further supports a role of Wnt signaling in disease pathogenesis.

• #15 Histopathology of intersymphyseal band and its correlation with continence in bladder exstrophy repair | Annals of Pediatric Surgery | Full Text

  https://aops.springeropen.com/articles/10.1186/s43159-021-00126-3

  The smooth muscle of the bladder neck, we believe, is the keystone to remaining dry as the bladder begins to distend with urine up to the point of voluntary voiding or attaining full capacity. […] Having emphasized the importance of the bladder neck smooth muscle, we stress that it is represented by the intersymphyseal band (ISB) in exstrophy patients. This is proved by demonstrating smooth muscle in histopathological sections taken from the ISB during surgery. This band essentially provides the dynamic outlet resistance required in the process of achieving continence. […] The ISB represents the smooth muscle of the bladder neck in patients of exstrophy. […] This band with its intact nerve supply needs to be wrapped around the bladder neck during the primary repair itself to preserve the smooth muscle that it contains. A well-constructed bladder outlet is one of the important factors to give the best chance for development of the bladder as well as acceptable social continence. […] Repeated surgeries that involve dissection in this area replace the smooth muscle of the ISB with fibrosis which then has a direct impact on continence. Hence, successful single-stage repair should be the aim of reconstruction.

• #15 Histopathology of intersymphyseal band and its correlation with continence in bladder exstrophy repair | Annals of Pediatric Surgery | Full Text

  https://aops.springeropen.com/articles/10.1186/s43159-021-00126-3

  Urinary incontinence is a major problem in operated exstrophy patients. […] The purpose of this study is to establish the nature of tissue the ISB is composed of. This can be used to determine its role in the surgical management of exstrophy epispadias complex (EEC) patients. […] A significant percentage of patients in whom this band was reconstructed around the bladder neck gradually became continent/partly continent with an increase in the dry interval with time. […] It can be a considerable factor to pay attention to the step of wrapping the ISB around the bladder neck during EEC repair. This serves to function as the smooth muscle of the bladder neck as proven histologically in our operated patients. It may have a role to support future continence in these patients. […] Our study thus hypothesizes that the ISB represents nothing but the smooth muscle of the bladder neck and plays a significant role in making operated EEC patients continent.

• #16

  https://www.africanurology.com/index.php/au/article/view/152

  Bladder exstrophy-epispadias-cloacal exstrophy complex (BEEC) is a spectrum of congenital urologic anomalies that involve the bladder, urethra, genitalia, and pelvic musculoskeletal system, and can affect urinary continence, sexual health, and fertility. […] There have been significant insights into the aetiology of BEEC in the last decade. Specifically, recent genetic studies have suggested that downstream regulator(s) of p63, Isl1, and other genes may play a role in the failure of the lower urinary tract to close. […] We summarise the epidemiology of this rare complex including what is known about its incidence in Africa before presenting recent advances in comparative genetics from mouse models and human studies that provide insights into BEEC pathogenesis.

• #17 Bladder exstrophy – Wikipedia

  https://en.wikipedia.org/wiki/Bladder_exstrophy

  Bladder exstrophy is a congenital anomaly that exists along the spectrum of the exstrophy-epispadias complex, and most notably involves protrusion of the urinary bladder through a defect in the abdominal wall. […] The underlying embryologic mechanism leading to bladder exstrophy is unknown, though it is thought to be in part due to failed reinforcement of the cloacal membrane by underlying mesoderm. […] The cause is not yet clinically established but is thought to be in part due to failed reinforcement of the cloacal membrane by underlying mesoderm.

• #18 Cited

  https://www.koreamed.org/SearchBasic.php?RID=2139394

  The pathogenesis of bladder and cloacal exstrophy is an abnormal development of the cloacal membrane. […] The incidence of each is one in l0,000-50,000 and 200,000-400,000 live births. […] Male is more commonly affected than female. […] Analyzing the factors that contribute to the development of embryological classical type of bladder exstrophy.

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