New Insights on the Basic Science of Bladder Exstrophy-epispadias Complex.

The exstrophy-epispadias complex is a rare congenital anomaly presenting as a wide spectrum of disorders. The complex nature of this malformation leads to continuous investigations of the basic science concepts behind it. Elucidating these concepts allows one to fully understand the mechanisms behind the disease in order to improve diagnosis, management, and treatment ultimately leading to improvement in patient quality of life. Multiple technological advancements within the last 10 years have been made allowing for new studies to be conducted. Herein, the authors conduct a literature review of studies from 2009 to 2019, considering novel theories regarding the genetics, embryology, bladder, bony pelvis, prostate, and genitalia of patients with bladder exstrophy-epispadias complex.

The intravesical phallus in patients with cloacal exstrophy: An embryologic conundrum.

BACKGROUND: Phalluses present inside the extrophied bladder of cloacal exstrophy (CE) newborns have been sporadically reported in the literature; this clinical entity has largely unknown origins and may represent an extremely rare anomaly of CE. OBJECTIVE: Along with nearly doubling the number of reported intravesical phalluses in the literature, this study aims to outline the common anatomic features and discuss the implications for theories of CE embryogenesis. STUDY DESIGN: The authors retrospectively identified patients with CE and a potential intravesical phallus between 1997 and 2017 at two high-volume centers. Information was obtained about karyotype, age at closure, neurologic and renal anomalies, diastasis, phallus anatomy, and phallus biopsy pathology. RESULTS: Six genotypic males met the inclusion criteria. Five of six had a diastasis greater than 6 cm. Four of six had paired corporal bodies in the intravesical phallus, one had a single corporal body, and one had a corporal-like structure. Five of six patients had a phallus located midline in the caudal aspect of the bladder; one was located midline in the bladder dome. Phallic biopsies were obtained in three of six patients. Two showed glanular and corporal tissue while the other showed vascular proliferation morphologically similar to that of erectile tissue. DISCUSSION: Previous reports suggested that a superior vesicle fissure configuration, fusion of the corporal bodies, and fused bladder plates were common findings with an intravesical phallus. With the addition of new cases, the only consistent variable between patients is a phallus located anywhere along the bladder plate that can comprise a corporal-like structure, a single corporal body, or fused corporal bodies. These findings have implications for several embryologic theories. Although this is a retrospective review with a limited number of patients, the condition is exceedingly infrequent making it only observable retrospectively over decades at high volume centers. CONCLUSIONS: The study outlined common anatomic features of the intravesical phallus in cloacal exstrophy and discussed the subsequent embryologic implications. In cloacal exstrophy newborns with presumed aphallia, meticulous inspection of the bladder plate and biopsy of any potential phallic structures can prevent resection of phallic tissue.

Early Diagnosis of Bladder Exstrophy: Quantitative Assessment of a Low-Inserted Umbilical Cord.

OBJECTIVES: Bladder exstrophy is a rare severe congenital malformation. Early prenatal diagnosis is scarcely described in the literature. Low insertion of the umbilical cord is a constant anatomic feature of bladder exstrophy. The aim of our study was to assess whether early measurements of the umbilical cord insertion-to-genital tubercle length may serve as quantitative measurements for a low-inserted umbilical cord in cases of bladder exstrophy. METHODS: The umbilical cord insertion-to-genital tubercle length was prospectively measured in all cases referred for a nonvisualized urinary bladder before 18 weeks' gestation. Final diagnoses were compared with prenatal measurements. RESULTS: Fifteen fetuses were evaluated for a nonvisualized bladder at a mean gestational age of 15.7 weeks (range, 14-17 weeks). Of them, 6 cases were diagnosed with bladder exstrophy, and 9 cases had a normal urinary bladder. All cases with bladder exstrophy had an umbilical cord insertion-to-genital tubercle length below the fifth percentile for gestational age, whereas cases with a normal bladder had a normal measurement. CONCLUSIONS: Fetuses with bladder exstrophy have an umbilical cord insertion-to-genital tubercle length below the fifth percentile of the general population. This measurement may serve as a complementary objective sonographic parameter in the prenatal assessment and counseling of cases suspected of having bladder exstrophy during early pregnancy.

When Closure Fails: What the Radiologist Needs to Know About the Embryology, Anatomy, and Prenatal Imaging of Ventral Body Wall Defects.

Ventral body wall defects (VBWDs) are one of the main categories of human congenital malformations, representing a wide and heterogeneous group of defects sharing a common feature, that is, herniation of one or more viscera through a defect in the anterior body wall. Gastroschisis and omphalocele are the 2 most common congenital VBWDs. Other uncommon anomalies include ectopia cordis and pentalogy of Cantrell, limb-body wall complex, and bladder and cloacal exstrophy. Although VBWDs are associated with multiple abnormalities with distinct embryological origins and that may affect virtually any system organs, at least in relation to anterior body wall defects, they are thought (except for omphalocele) to share a common embryologic mechanism, that is, a failure involving the lateral body wall folds responsible for closing the thoracic, abdominal, and pelvic portions of the ventral body wall during the fourth week of development. Additionally, many of the principles of diagnosis and management are similar for these conditions. Fetal ultrasound (US) in prenatal care allows the diagnosis of most of such defects with subsequent opportunities for parental counseling and optimal perinatal management. Fetal magnetic resonance imaging may be an adjunct to US, providing global and detailed anatomical information, assessing the extent of defects, and also helping to confirm the diagnosis in equivocal cases. Prenatal imaging features of VBWDs may be complex and challenging, often requiring from the radiologist a high level of suspicion and familiarity with the imaging patterns. Because an appropriate management is dependent on an accurate diagnosis and assessment of defects, radiologists should be able to recognize and distinguish between the different VBWDs and their associated anomalies. In this article, we review the relevant embryology of VBWDs to facilitate understanding of the pathologic anatomy and diagnostic imaging approach. Features will be illustrated with prenatal US and magnetic resonance imaging and correlated with postnatal and clinical imaging.

Pathogenesis of bladder exstrophy: A new hypothesis.

UNLABELLED: Classical bladder exstrophy affects 1 in 30 000 live births. Results of surgical treatment from different institutions employing various surgical techniques are not uniform, thus there is a need for a consensus on the best technique for bladder exstrophy repair. 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. The anatomy of exstrophy shows that the infraumbilical abdominal wall, the anterior wall of the bladder, and the urethra are split, with splayed out genitalia and musculature along with pubic diastasis. There is no tissue loss and hence embryological defect is unlikely to be the cause of bladder exstrophy. Thus there is a need to examine pathogenesis of bladder exstrophy. METHODS: A literature search was made of the various hypotheses for cause of bladder exstrophy, and attempts were made to propose a new hypothesis. The present hypothesis is also the basis for a technique of mobilization of pelvic musculature, done in two stages. RESULTS: The functional outcomes of 38 children with bladder exstrophy managed over a period of 10 years were reviewed. At a mean follow-up of 4.5 years (range 2.5-8 years), 82% of patients were functionally continent. CONCLUSIONS: The exact embryopathogenesis of bladder exstrophy is unknown. In this study a new hypothesis is proposed, with the aim of tailoring the surgical procedure to correct this defect. 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.

Unusual duplicate bladder exstrophy in a female newborn: a case report.

The authors report a rare variant of exstrophy-epispadias complex, a duplicate bladder with normal bladder communicating with an exstrophic bladder by a fistula, in a girl with no genital malformation except for a duplicated clitoris. This variant could be a hybrid form of duplicate bladder exstrophy and superior vesical fistula. It seems easier to repair and has a better prognosis than classic bladder exstrophy.

Antenatal diagnosis of bladder/cloacal exstrophy: challenges and possible solutions.

OBJECTIVE: To identify the pitfalls in accurate antenatal diagnosis of bladder exstrophy (BE) and cloacal exstrophy (CE), and thus understand the challenges for antenatal counselling. METHODS: A prospectively maintained bladder exstrophy database of antenatal and live born referrals for BE/CE was used to identify patients. Data were collected about the antenatal scan findings and the outcome of pregnancy. RESULTS: Between 2003 and 2009, 40 new babies with BE/CE were referred and of them 10 had an antenatal diagnosis. Five patients did not have a diagnosis despite suspicious findings noted on antenatal scans and another three had a wrong diagnosis of BE/CE. Of the 16 referrals with antenatal suspicion of BE/CE, 5 opted for termination. At the 20-week scan, it was possible to identify the gender of the fetus in 3/16 cases only. CONCLUSIONS: Only a quarter of the babies born with BE/CE had received an antenatal diagnosis. Raising awareness about the condition amongst radiographers, and facilitating further scanning by a specialist fetal management unit if suspicious findings are noted, is crucial for improving the rate of detection. An antenatal diagnosis may not be reliable, and difficulty in identifying gender at the 20-week scan adds to the complexity of antenatal counselling. Magnetic resonance imaging and karyotyping may provide additional helpful information.

Deciphering caudal embryonic defects: embryological analysis and reviewing literature data.

BACKGROUND: A number of syndromes÷associations involving the caudal region have been described in the literature. Each of them is characterized by a set of morphological features. Reports on difficulties in delineation and an ever-increasing constellation of defects in recent past call for a comprehensive study into the morphologic presentations and pathogenesis of caudal embryonic defects. MATERIALS AND METHODS: The present article describes a case of the OEIS complex--a combination of omphalocele, exstrophy of bladder, imperforate anus and spinal defects. Literature search was performed and morphologic presentations, as described in literature, of all syndromes and associations affecting the caudal region of the embryo have been compared. Morphologic presentations were analyzed embryologically. RESULTS: A remarkable overlap of symptom complex was observed. Embryological analysis of the phenotypic presentations of all these syndromes points towards a common pathogenesis, early in the embryonic life. The embryologic analysis suggests that these defects are a result of defects in proliferation, migration or subsequent differentiation of any of the three subdivisions of intra-embryonic mesoderm. CONCLUSIONS: Based on the analysis a new hypothesis for the causation of caudal defects is proposed. This hypothesis suggests that a local internal environmental imbalance, at the site of implantation, can cause nutritional insult to the embryo during gastrulation, during the third and the early fourth week of embryonic life.

Embryology and bony and pelvic floor anatomy in the bladder exstrophy-epispadias complex.

The exstrophy-epispadias complex is a complex congenital anomaly that, although rare, remains the largest genitourinary birth defect that is surgically correctable. The primary defect in exstrophy is a derangement in midline developmental that presents with a spectrum of severity. In its mildest form, epispadias, the dorsal urethral unit is not fused and has failed to form into a tube. Next, patients with classic bladder exstrophy present with a bladder and urethra open and continuous with the abdominal wall; also associated is a failure of the abdominal muscles, pelvic ring, and pelvic floor musculature to fuse in the midline. Cloacal exstrophy, the most severe variant, includes exstrophied hindgut tube and a more severe degree of concomitant congenital derangements of musculoskeletal, genitourinary, gastrointestinal, and neurological systems. The embryology of the exstrophy-epispadias complex has been long studied, yet debate still exists over the specific origins of the anomaly. This article covers the embryologic theories of this congenital defect and the subsequent bony pelvic and pelvic floor muscular defects characteristic of exstrophy. Primarily, the anatomic focus will be on classic bladder exstrophy because it is the most common and well studied to date.

Measurement of the fetal umbilical cord insertion-to-genital tubercle length in early gestation: in utero sonographic study.

OBJECTIVES: The purpose of this study was to establish in utero reference ranges for the fetal umbilical cord insertion-to-genital tubercle length in early gestation. METHODS: A prospective cross-sectional study was performed on 140 normal low-risk singleton pregnancies between 12 and 18 weeks' gestation. The umbilical cord insertion-to-genital tubercle length was measured in a midsagittal section with high-resolution transvaginal or transabdominal sonography. The mean and 95% prediction limits were defined for each gestational week and analyzed by regression equations and correlation coefficients. RESULTS: Adequate measurements were obtained in 134 patients. The umbilical cord insertion-to-genital tubercle length as a function of gestational age was expressed by the following regression equation: umbilical cord insertion-to-genital tubercle length = -3.079452 + 1.09 × week (R(2) = 0.7117). The correlation R(2) = 0.7117 was found to be highly statistically significant (P < .001). The normal mean and 95% prediction limits were defined for each gestational week. During the study period, 2 cases were referred to our unit because of nonvisualization of the urinary bladder. The umbilical cord insertion-to-genital tubercle lengths in these cases were below the 95th percentile, confirming the diagnosis of bladder exstrophy. CONCLUSIONS: The normative data established in this study may be helpful for early pre-natal diagnosis congenital bladder exstrophy.

Partial umbilical exstrophy with cecal patch and intact hindgut entering a cloaca: a new variant.

Variants of cloaca and exstrophy are difficult to explain and manage. We describe a female neonate having partial umbilical exstrophy with a cecal patch in the bladder and an intact distal hindgut that was expressed as a cloaca. The baby was managed by ileostomy and bladder closure without separating the cecal patch from the bladder. The possible embryological origin of this abnormality is discussed, and the literature is reviewed.

p63 (TP73L) a key player in embryonic urogenital development with significant dysregulation in human bladder exstrophy tissue.

Human bladder exstrophy-epispadias complex (BEEC) comprises a spectrum of urogenital anomalies in which part or all of the distal urinary tract fails to close. Several lines of evidence implicate genetic factors in the formation of BEEC. Among them a murine p63+/+ knockout model showed the full picture of classic exstrophy of the bladder and other urogenital defects within the BEEC spectrum. This led us to study in depth the role of p63 in urogenital development in mice and investigate the implication of p63 in human BEEC. Whole mount in situ analysis in mice was carried out to investigate the ventro-caudal expression of the p63 transcript at gestational days (GD) 9.5-12.5, the equivalent of human gestational weeks 4-6 (postulated time of BEEC organogenesis in humans). In addition, p63 expression analysis was performed in human blood and bladder derived samples of 15 BEEC newborns accompanied by sequencing analysis of their genomic DNA. We also conducted sequencing analysis of genomic DNA in additional 22 BEEC patients. In mouse embryos, p63 expression was detected at days 9.5-12.5 in the cloacal membrane and urethral epithelium, supporting its role in the morphogenesis of the external genitalia and the bladder. Tissue-specific expression of a novel and already-known mRNA isoforms were established and a reproducible dysregulation of variable p63 isoforms was observed in 11 of 15 patients indicating altered gene expression. However, no obvious p63 gene mutations were identified in any of the patients. Our findings strongly suggest that p63 is not only involved in embryonic formation of the urogenital and ventrocaudal anatomy but is also highly dysregulated in human BEEC bladder tissue. Since p63 has been shown to self-regulate its expression through a balance of its isoforms, the dysregulation observed may contribute to the formation of BEEC.

[Prenatal diagnosis and management of isolated bladder exstrophy]. / Diagnostic anténatal et prise en charge des extrophies vésicales isolées.

The isolated bladder extrophy is a major congenital malformation which prenatal diagnosis is essential. It is based on the non-visualization of the bladder during the first trimester ultrasound but in most cases, it is confirmed by the morphological ultrasound of the second trimester. For the baby, the prognosis of life quality depends on the accurate identification of the malformation, the foetal sex and the associated pathologies. Thus, a detailed ultrasound evaluation is necessary and requires an operator experienced in the search of malformations. As this abnormality has important aesthetic and functional consequences, a multidisciplinary management is required for a good information of the couple. The continuation of pregnancy is currently possible but the couple should be informed that after surgery, often a major one, more than 75% of children will have a urinary continence by reconstruction or bypass. Furthermore, their ability of reproduction will need to be medically improved.

Ruptured rectal duplication cyst with classical bladder exstrophy.

A newborn boy was brought to us, 2 hours after birth, with a mucosal-lined left hemiperineal lesion associated with classical bladder exstrophy and an anterolaterally displaced anus. Perineal anatomy was restored by excising the mucosa lined lesion. The bladder closure for classical bladder exstrophy was done at the same time. Histologically, gastric, respiratory, and small intestinal epithelia were present in the mucosa. A rectal duplication cyst that had ruptured in utero through the hemiperineum could explain the anomaly. The association of classical bladder exstrophy with ruptured rectal duplication cyst has never previously been described in the literature.

The embryologic origin of ventral body wall defects.

Ventral body wall defects include ectopia cordis, bladder exstrophy, and the abdominal wall malformations gastroschisis and omphalocele. The etiology of ectopia cordis, gastroschisis, and bladder exstrophy is not known, but they may be linked to abnormalities in the lateral body wall folds responsible for closing the thoracic, abdominal, and pelvic portions of the ventral body wall. These folds form in the fourth week (postfertilization) of development as a combination of the parietal layer of lateral plate mesoderm and overlying ectoderm and must move ventrally to meet in the midline. There are differential rates of cell proliferation in the folds and asymmetries in their movement that may be involved in teratogenic effects of toxic factors. Also, the fusion process between the folds is complex, involving cell-to-cell adhesion, cell migration, and cell reorganization and all of these phenomena may be targets for disruption, leading to malformations. In this regard, closure of the ventral body wall is likened to neural tube closure and involves similar processes. It also encompasses a similar time frame during development, such that most neural tube and ventral body wall defects have their origins during the fourth week of development. Omphalocele is a separate entity whose etiology is known. This defect is attributed to a failure of gut loops to return to the body cavity after their normal physiological herniation into the umbilical cord from the 6th to 10th week of development. Thus, the origin of this defect is completely different from that of the ventral body wall malformations.

Cloacal exstrophy: a comprehensive review of an uncommon problem.

OBJECTIVE: To provide a comprehensive overview of the clinical features, diagnosis, current management strategies, and outcomes of cloacal exstrophy. METHODS: A PUBMED/Medline search of the literature was performed on cloacal exstrophy focusing on associated anomalies, treatment, and quality of life issues. RESULTS: The incidence of cloacal exstrophy is between 1 in 200,000 and 400,000 live births. Survival rates now approach 100% secondary to improved understanding of underlying abnormalities and advances in neonatal care and surgical technique. Important principles of initial management include proper nutritional support, early closure of exstrophy, and preservation of intestinal length. The achievement of urinary and fecal continence remains a challenge. Data for long-term outcomes are now emerging which provide new insight into issues of gender identity, function, and psychosocial development of these patients. CONCLUSION: Cloacal exstrophy remains a rare and complex congenital anomaly, characterized by an array of anatomical defects affecting multiple organ systems. A multidisciplinary approach to management is advocated with a focus on optimization of patient function and quality of life.

The exstrophy-epispadias complex.

Exstrophy-epispadias complex (EEC) represents a spectrum of genitourinary malformations ranging in severity from epispadias (E) to classical bladder exstrophy (CEB) and exstrophy of the cloaca (EC). Depending on severity, EEC may involve the urinary system, musculoskeletal system, pelvis, pelvic floor, abdominal wall, genitalia, and sometimes the spine and anus. Prevalence at birth for the whole spectrum is reported at 1/10,000, ranging from 1/30,000 for CEB to 1/200,000 for EC, with an overall greater proportion of affected males. EEC is characterized by a visible defect of the lower abdominal wall, either with an evaginated bladder plate (CEB), or with an open urethral plate in males or a cleft in females (E). In CE, two exstrophied hemibladders, as well as omphalocele, an imperforate anus and spinal defects, can be seen after birth. 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. Diagnosis at birth is made on the basis of the clinical presentation but EEC may be detected prenatally by ultrasound from repeated non-visualization of a normally filled fetal bladder. Counseling should be provided to parents but, due to a favorable outcome, termination of the pregnancy is no longer recommended. Management is primarily surgical, with the main aims of obtaining secure abdominal wall closure, achieving urinary continence with preservation of renal function, and, finally, adequate cosmetic and functional genital reconstruction. Several methods for bladder reconstruction with creation of an outlet resistance during the newborn period are favored worldwide. Removal of the bladder template with complete urinary diversion to a rectal reservoir can be an alternative. After reconstructive surgery of the bladder, continence rates of about 80% are expected during childhood. Additional surgery might be needed to optimize bladder storage and emptying function. In cases of final reconstruction failure, urinary diversion should be undertaken. In puberty, genital and reproductive function are important issues. Psychosocial and psychosexual outcome depend on long-term multidisciplinary care to facilitate an adequate quality of life.

Fetal bladder wall regeneration with a collagen biomatrix and histological evaluation of bladder exstrophy in a fetal sheep model.

OBJECTIVES: To evaluate histological changes in an animal model for bladder exstrophy and fetal repair of the bladder defect with a molecular-defined dual-layer collagen biomatrix to induce fetal bladder wall regeneration. METHODS: In 12 fetal lambs the abdominal wall and bladder were opened by a midline incision at 79 days' gestation. In 6 of these lambs an uncorrected bladder exstrophy was created by suturing the edges of the opened bladder to the abdominal wall (group 1). The other 6 lambs served as a repair group, where a dual-layer collagen biomatrix was sutured into the bladder wall and the abdominal wall was closed (group 2). A caesarean section was performed at 140 days' gestation, followed by macroscopic and histological examination. RESULTS: Group 1 showed inflammatory and maturational changes in the mucosa, submucosa and detrusor muscle of all the bladders. In group 2, bladder regeneration was observed, with urothelial coverage, ingrowth of fibroblasts and smooth muscle cells, deposition of collagen, neovascularization and nerve fibre formation. This tissue replaced the collagen biomatrix. No structural changes of the bladder were seen in group 2. CONCLUSIONS: The animal model, as in group 1, for bladder exstrophy shows remarkable histological resemblance with the naturally occurring anomaly in humans. This model can be used to develop new methods to salvage or regenerate bladder tissue in bladder exstrophy patients. Fetal bladder wall regeneration with a collagen biomatrix is feasible in this model, resulting in renewed formation of urothelium, blood vessels, nerve fibres, ingrowth of smooth muscle cells and salvage of the native bladder.