Bladder Agenesis: A Systematic Review

Bladder agenesis is a rare congenital deformity characterized by the absence of the bladder. It is primarily observed in postmortem dissections of stillbirths rather than live births. The condition is often associated with other congenital anomalies, leading to the hypothesis that most affected fetuses do not survive to term. However, the exact cause and specific associated anomalies remain unclear and poorly described in the literature. The limited mention of bladder agenesis in textbooks and literature underscores the importance of creating a comprehensive source for future research in this field. Therefore, our objective is to collect and analyze data on bladder agenesis, focusing on associated anomalies and potential causes, to enhance our understanding of the condition. We conducted a thorough review of reports collected from three databases, Google Scholar, PubMed, and Science Direct, last searched on July 30, 2023, starting with 327 reports. Excluding duplicates and records written in languages other than English, veterinary studies, irrelevant reports, or stillbirths. Inclusion criteria were the following: cases must have proven bladder agenesis, not hypoplasia, and must have most of the information, including the age of diagnosis, presenting symptoms, gender, associated anomalies, and management or outcome of the patient. A quality assessment was conducted according to the Joanna Briggs Institute checklist for case reports. A total of 65 case reports from 56 articles were included in the review. Through our manual analysis, we documented a wild array of malformations associated with bladder agenesis. Among the reports reviewed, 93% exhibited urinary system malformations beside bladder agenesis, 77% were found to have reproductive malformations, 44% had gastrointestinal anomalies, 38% showed musculoskeletal malformations, 28% had cardiac malformations, and another 28% had vascular anomalies. The overall mortality rate was 38%, with a higher rate of 74% for males compared to 20% for females. By collating and analyzing those case reports, we aim to contribute to a better understanding of bladder agenesis and its associated anomalies, facilitating further investigations and advancements in the field.


Introduction And Background
Throughout the years, there have been few reported cases of bladder agenesis, with the earliest mention dating back to 1654 by Rhodius.It is difficult to pinpoint an accurate number of cases that have been reported since then.There have been few citations of live births in English literature, for which it has been considered an extremely rare condition, especially given that it has been associated with numerous anomalies, some of which are fatal.

Review Methodology
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines (Figure 1 and Tables 1, 2).The search last conducted on July 30, 2023, encompassed three prominent databases: Google Scholar, PubMed, and ScienceDirect.Our query focused on case reports, utilizing precise keywords, including "bladder agenesis," "-gall," and "gallbladder."A comprehensive screening process was undertaken by a single reviewer to eliminate duplicate entries, publications in languages other than English, studies involving animal models, and articles that were irrelevant or inaccessible in full text.Furthermore, we exercised prudence in excluding articles related to stillbirths, intrauterine scans, urinary bladder hypoplasia, and those presenting insufficient data for analysis.In addition, articles that reported the same case were analyzed for further details without duplication within the statistical analysis.To include a study, it must specify that it was indeed a case of bladder agenesis and include most, if not all, of the following information: age of diagnosis, presenting symptom, gender, associated anomalies, and management or outcome of the patient.Additionally, a quality assessment of the reports was conducted according to the Joanna Briggs Institute (JBI) critical appraisal tools for systematic reviews, using their checklist for case reports (Table 3).The data were manually collected and sorted in a tabular manner in Excel (Microsoft Corporation, Redmond, WA) for easier data extraction and comparison.List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, and analyses), and if not, the methods used to decide which results to collect.
List and define all other variables for which data were sought (e.g.participant and intervention characteristics and funding sources).Describe any assumptions made about any missing or unclear information.

Methodology
Study risk of bias assessment 11 Specify the methods used to assess the risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

Methodology
Effect measures 12 Specify for each outcome the effect measure(s) (e.g.risk ratio and mean difference) used in the synthesis or presentation of results.N/A

Synthesis methods 13a
Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item 5)).
N/A 13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.Methodology 13c Describe any methods used to tabulate or visually display the results of individual studies and syntheses.Methodology 13d Describe any methods used to synthesize results and provide a rationale for the choice(s).If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

Methodology 13e
Describe any methods used to explore possible causes of heterogeneity among study results (e.g.

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.

Epidemiology
Most reports were from India with 14 cases, followed by the USA with 13 cases, Türkiye with eight, Italy with three, and Iran and Mexico with two reports each.One report was from each of the following countries: Germany, France, Poland, South Africa, Japan, Taiwan, Pakistan, KSA, UK, Switzerland, and Canada.The origin could not be determined in three cases.
It has been reported in some of the previous literature that the female-to-male ratio is 30:1.The reviewed reports had 19 males out of the 65 (two were of undermined gender), making the ratio 2.3:1.This female predominance has been attributed to the higher severity of associated anomalies in males, leading to intrauterine dismissal.Only seven subjects had a twin, five of whom were monozygotic [14,15,21,34,39], and one via in vitro fertilization [32].One has hypospadias [21], one, similarly to their twin, has teratology of Fallot [14], and five were without complaint [15,29,32,37,45].
The mean age of presentation was approximately 4.5 years, with a median of 10 days and a mode of 0, with 32 subjects presenting at birth.The oldest subject was 60 years old at the time of the presentation.

Classifications
Metoki et al. [7] classified bladder agenesis according to the site of ureter insertion into five types in females: With 44 females, 21 were reported to have the vagina as the insertion site [1,2,5,6,11,24,27,30,[32][33][34][35]37,[41][42][43][51][52][53], accounting for 48% of the female cases; the urogenital sinus in nine cases or 21% of female cases [6,9,12,15,23,40,44,46], three cases reported the common cloaca as the site of insertion by Jain et al. [29] and ectopically to the skin at the natal cleft [16] or uterus [19].Karaguzel et al. reported a case in which the subject had a blind pouch between the natal cleft and the coccyx, presumed to be of the anus, from which some urine was draining [20].One case had bilateral renal and ureteric agenesis [29].The remainder of the cases did not mention the site of insertion (Table 4).Of the 19 male subjects, five were not investigated for the sites of insertion [14,25,36,45,47]; three were reported with the rectum as the site of insertion [22,26,28]; and another case had no apparent outlet but had a fibrous cord connecting to the rectum [17].Three subjects had ureters attached to the urethra [13,18,31] and one to the seminal vesicle [54].Those four latter cases represent the urogenital sinus type.Two cases reported the common cloaca as the site of insertion [29,56].In one case, the ureters were blind-ended [8].Three cases reported bilateral renal agenesis (Table 4) [21,38,39].
The period of infancy is a mixture.Graham had a subject at six weeks of age with failure to gain weight with both UTI and azotemia in addition to high blood pressure [4].Similarly, in another study by Savanelli et al., the subject presented at four weeks with ambiguous genitalia, azotemia, and UTI [23].Cases of UTI were noted as early as the first month [10,32].One subject had recurrent UTIs at the age of three months [34].Metoki et al.'s subject presented at four months with urogenital abnormalities, azotemia, and metabolic acidosis [7], and a case of continuous dribbling at nine months by Sailo and Sailo [44].

Associated Anomalies
Bladder agenesis has been found to be associated with a wide array of malformations, including those of the urogenital system, cardiovascular system, musculoskeletal system, and gastrointestinal system (Table 4).
Esophageal atresia was reported in four cases [8,14,29,41]; in two of them, a distal tracheoesophageal fistula was observed [8,29].Making the number of cases with GI malformations 29, or 44% of the total cases.

Vascular Anomalies
In our review, we found 18 cases have been reported to have vascular anomalies, 28% of reports (Table 4), and eight of them had a single umbilical artery [8,14,29,38,39,49,56].Dykes et al. reported in 1993 a case series study of subjects having urogenital malformations with distorted distal aortas or iliac arteries, one of whom had bladder agenesis with the aberrant aorta low in the pelvis giving rise to an aberrant left iliac artery and a left internal iliac branch absent [12].An aberrant vascular artery connecting the right internal iliac artery to the left external iliac artery has been documented in two cases by Lowrey et al., in addition to an absent left common iliac artery in one subject [50].Indiran et al. reported a case in which the subject had a high bifurcation of the aorta with the right external iliac artery, giving rise to what seems to be the posterior trunk of the right internal iliac artery in association with right developmental dysplasia of the hip (DDH) and gluteal muscular atrophy [35].In a follow-up to Rodin et al.'s report, a more detailed description of the vascular anomaly was mapped, starting below the level of the superior mesenteric artery, where the abdominal aorta branches into two vessels; the smaller of the two is thought to be the distal portion of the abdominal aorta, and the larger vessel is thought to be the aberrant abdominal umbilical artery, continuing to the left as the iliac and common femoral artery.Additionally, giving a branch to the right communicates with the atretic distal aorta.It was noted that both internal iliac arteries were absent as well [57].
Vakili documented in 1973 an absent left common iliac artery and the internal and external left iliac arteries rising directly from the aorta [5].It was reported by Kaefer and Adams that a subject had a duplicated aorta and a common vessel connecting the two internal iliac arteries [17].Nazer et al.'s subject had a low bifurcation of the aorta, and the internal iliac arteries were absent [51].Akdas et al. found that the subject had an absent right renal artery [11].Lastly, an esophageal ring is formed by the left aortic arch and a posteriorly coursing aberrant right subclavian artery [46].
Those patients were not reported to have neurological deficits, all but one of whom had spinal bifida and scoliosis with decreased Achilles reflexes and sensations of pain, temperature, and touch [1].Atıcı et al. had a case of mermaid syndrome (sirenomelia), with two femurs, two tibia, one fibula, one foot, and four toes; the upper limbs were without observable anomalies [49].Another case was reported by Pandey et al. to have partial sacrococcygeal agenesis, a single lower limb, a short tibia, and absent fibula, ankle, and foot bones [39].
Out of 65 cases, 25 had muscular, skeletal, and/or neurological anomalies, or 38% of all cases.

Urinary System Anomalies
Out of the 65 cases, 61 (approximately 94%) had urinary abnormalities other than bladder and urethral agenesis.Not all cases reported had urethral agenesis.

Kidneys
Abnormalities involving the kidneys consisted mostly of hydronephrosis and absent kidneys, as well as cysts or dysplasia.There were a couple of cases of fused kidneys [12,45], and a single case of duplex kidneys [25].
A third kidney was reported in one instance [22].At least some degree of renal impairment has been noted in 21 cases; in some cases, it was mild; in others, it led to the death of the subject.We speculate the number to be higher, as some of the subjects with more severe anomalies passed away within minutes or hours of birth, most commonly from pulmonary hypoplasia due to oligohydramnios.One reported proteinuria [15].Three subjects were found to have hypertension; all three had a single kidney, and two had recurrent UTI; one improved after nephrostomy [4], another had refractory hypertension [26], and the third had grade II retinopathy [11].

Genital Abnormalities
Males: With a total of 19 males, only two subjects had normal external genitalia for males [18,26], translating to a rate of 90% of all male reports.The malformations observed were of penoscrotal transposition in five cases [14,17,25,28,55], two of which also had a bifid scrotum: one reported descended gonads [55], the other mentioned thick vas deferens [28].Kaefer and Adams reported one of the cases of penoscrotal transposition, in which the subject had a normal scrotum with descended testes but a small skin tag as a phallus, thus assigning a female gender despite having a karyotype of XY46 [17].The absent phallus was noted in eight subjects, with an absent scrotum [39], an underdeveloped scrotum was noted twice [8,36], a normal scrotum [21,22,47,56], the latter reported one atrophic testis, and lastly, cryptorchidism [29] and hypospadias [13].In one instance, the phallus was reported to be distended, with an absent scrotum and palpable testes [45].The last case did not mention any information about genitalia [31].
Females: Ambiguous genitalia have been reported in 13 subjects [6,7,9,23,29,41,46,50,51], mostly hypertrophied clitoris or protruding skin folds.Absent labia majora and hypoplasia of the labia minora have been reported in one of the cases by Tortora et al. [6].One case had transposition of the external genitalia: posteriorly displaced clitoris and anus with a pubic dimple [41]; similarly, another had fused labia majora with a posteriorly placed skin tag and an absent clitoris [46].
There are 31 reported cases with internal or external genital abnormalities, representing 70% of all female cases.
There were two cases where the gender of the newborn was undetermined, as they lacked any external genitalia and neither a karyotype nor autopsy were performed [49,54].

Miscellaneous
Palmer and Russi's patient was reported to have café au lait spots [3].four skin tags anterior to one of her ears and a grade II goiter, in addition to an absent kidney and multiple musculoskeletal abnormalities [15].Ozcakir et al. reported a case of left choanal atresia in which the subject had severe oligohydramnios, leading to fatal lung hypoplasia [54].One of Tortora's subjects was found to have a cleft palate and strabismus [6].
Dusmet et al.'s subject had VATER; vertebral abnormalities included and were not limited to additional hemivertebrae and ribs, partial fusion, and scoliosis; anal atresia and imperforated anus; distal tracheoesophageal fistula with partial proximal esophageal atresia; tracheal cartilage anomalies; annular proximally; incomplete rings distally with partial stenosis; hypoplastic lungs; retroperitoneal ectopic adrenal tissue on microscopic examination; and wide dysplastic fontanelles.Additionally, he had dysmorphism: a broad flat nose, bilateral epicanthic folds, dysplastic low-set ears, redundant loose skin at the back of the neck, and a bilateral cleft lip with a cleft palate [8].
Dysmorphism was also noted by Khan and Walsh, with up-slanting palpebral fissures, a long philtrum, and a thin upper lip [43].One was reported to have Treacher Collins syndrome, with epicanthic folds, posterior angulation of the ears, dolichocephalous with a prominent occiput, and a short neck [22].Jain et al. reported a case with dysmorphic features, including a bilateral upward slant of the eyes, a depressed nasal bridge, and low-set ears.Three other cases were reported by them to have low-set ears, one of which had a webbed neck [29].
Continence was achieved by bladder construction from a sigmoid conduit with Mitrofanoff [33,37,40], or an ileocecum neobladder with Mitrofanoff [24,27,46,48,50], and an ileal pouch with Mitrofanoff [42].Ileocecum neobladder with anastomosis to the urethra with the use of the ileocecal valve as the neck of the bladder was performed in the case reported by Gopal [13].One case had laparoscopic Mainz II, in which the ureters are implanted into the rectosigmoid pouch and void via the rectum [52].

Prognosis
At the time of reporting, 25 subjects had expired (Table 6), most of whom passed away within the first year of life.There were 14 males, nine females, and two of undetermined gender.The mortality rate was 38% in total, with 74% for males and 20% for females.The risk of mortality was factored in by kidney function, urine output, and related complications, such as oligohydramnios resulting in pulmonary hypoplasia.Nine cases reported renal impairment of some degree [9,19,20,26,28,31,36,38,42].All six patients with bilateral renal agenesis passed away within hours of birth with respiratory insufficiency; notably, they all had complex congenital anomalies: VACTERL [38], mermaid syndrome [39,49], and urorectal septal malformation sequence [21,29,54].The case of VATER, who had bilateral renal dysplasia, also passed away 30 minutes after birth [8].In addition, sepsis and infections factored into the deaths of six subjects [6,16,20,26,28,36].Bowel perforation was the cause of death in one subject [29] and cardiac arrest in another [21].Prematurity was noted in 12 subjects as well; the youngest was 26 weeks old [49].The oldest patient at the time of presentation was a male at the age of 60 years, whose complaint was incontinence, for which he had fashioned a clip to be placed at his phallus.He is known to have some renal abnormalities but maintains normal kidney function.Interestingly, he has a child and has normal sexual function [18].
Females presenting at adulthood were five [1,3,11,43,52], their ability to reproduce is unknown.One was mentioned to have primary amenorrhea despite having a normal uterus but was noted to have polycystic ovaries [11].Another was described as having a bicornuate uterus, with one of the horns having endometrioma; she underwent menarche at 13 years of age and has been having four-to-seven-week cycles since [3].Gowtham et al. reported a case of a 20-year-old with labial adhesions, stenotic labial adhesions, and a unicornuate uterus.They reported the ovaries to be normal; it is unknown if she underwent menarche [52].Savanelli et al. followed one subject from infancy into puberty and reported her to be menstruating normally [23].
Eight subjects have failed to thrive; all but one had UTIs.However, that subject had renal failure, a cysticdysplastic kidney, and a corrected tetralogy of Fallot with pulmonary stenosis [50].Another subject had a cystic-dysplastic single kidney; she was given somatotropin, which aided her growth until she received a preemptive renal transplant, allowing her to continue to thrive [24].The remainder cases all had hydronephrosis [4,10,13,30,35].In one case, a subject had mild developmental delay; she was diagnosed at birth and received a renal transplant at three years of age [46].

Embryology
The bladder formation starts embryologically between the 4th and 7th weeks; the cloaca is divided by the urorectal spectrum into the rectum posteriorly and the urogenital sinus anteriorly; the latter divides into three segments [58]: the vesical part gives most of the bladder and is continuous with the allantois; the pelvic part gives the whole urethra in females and the prostatic part of the urethra in males; the phallic part gives the penis or the clitoris.
The allantois arises as a diverticulum of the yolk sac and is responsible for waste elimination and gas exchange.It also contributes to the formation of the umbilical cord, umbilical vessels, and placenta as it regresses between the 6th and 8th weeks of gestation, and the remnant is located between the two arteries within the cord.The intra-abdominal segment will constrict into the urachus, a thick, fibrous cord, and later obliterate to become the median umbilical ligament [59].
During embryonic development, initially the umbilical arteries branch ventrally from the dorsal aorta to the placenta in close association with the allantois.During the fourth week, a secondary connection forms from the common iliac arteries to the umbilical arteries, and it loses the primary dorsal aortic.After birth, the distal part of the umbilical artery obliterates, leaving the medial umbilical ligament, and the proximal part becomes the internal iliac arteries and superior vesical arteries [60].Interestingly, the developing kidney initially receives its blood supply from the common iliac arteries and later from the distal aorta [58].

Blood Supply
The blood supply of the bladder comes from the superior, middle, and inferior vesical arteries.The anterior division of the internal iliac artery gives rise to multiple arteries; the first is the umbilical artery, which gives rise to the superior vesical artery and the middle vesical, the latter may branch from the superior vesical [61].
The inferior vesical artery is a direct branch of the anterior division of the internal iliac artery; it may share a trunk with the middle rectal artery.In addition to supplying the inferior part of the bladder, the inferior vesical artery supplies the prostate, seminal vesicles, and sometimes the ductus deferens [62].On occasion, it might be a branch of the internal pudendal artery [63], and it is usually observed more commonly in males [64].The bladder may receive additional blood supply from the obturator artery and the inferior gluteal artery [62].The veins from the urinary bladder drain into the internal iliac vein [61].
The internal iliac artery has visceral and parietal branches; the visceral branches supply the urinary bladder, rectum, and urethra; in males, they additionally supply the prostate, ductus deferens, seminal vesicles, and ejaculatory ducts; and in females, they supply the uterus and vagina.The parietal branches supply musculoskeletal structures in the thigh, hip joint, and gluteal region [62].

Etiology
The exact pathogenesis of bladder agenesis is still unknown, and it is yet to be determined whether bladder agenesis and its associated malformations are due to a common etiology with high variability or whether different factors can lead to bladder agenesis.
Dykes et al. suggested that vascular abnormalities and bladder agenesis have the same underlying etiology [12], while Lowrey et al. propose that the organ's maldevelopment is provoked by vascular variations [50].
Research on the etiology of bladder agenesis is scarce.However, researchers have noticed overlapping with some syndromes or sequences involving caudal dysgenesis, and some of the reports we have reviewed were of bladder agenesis in association with the urorectal septal malformation sequence, VATER/VACTERL, sirenomelia, and Treacher Collins syndrome.
One of the theories dealing with caudal dysgenesis generally and sirenomelia specifically is vitelline vascular steal; vitelline vessels are branches of the dorsal aorta in the developing fetus and form a vascular network over the yolk sac.When a coalescence single large vitelline artery arising from the aorta assumes the function of the umbilical arteries and forms a single umbilical artery, the blood flow would be diverted to the placenta rather than the caudal portion of the embryo, leading to nutritional deficits and structural malformations [65].A severe type would result in lower limb amelia and the absence of the lower abdominal and pelvic structures, and a lesser form might lead to a wide variety of genitourinary and gastrointestinal defects [66].
A single umbilical artery (SUA) can be isolated when the normally derived umbilical arteries fuse prior to exiting the umbilical ring or when one of them gets atrophied [66].Depending on the number and types of vessels in the umbilical cord, SUA can be classified into four types [67]: type I: one allantoic umbilical artery (right or left), with the left umbilical vein (two vessels).Associated with central nervous system or genitourinary malformations, a short umbilical cord, and acarida.Type II: one vitellinic umbilical artery from the superior mesenteric artery, with the left umbilical vein (two vessels).Associated with caudal regression, sirenomelia, and anal agenesis.Type III: one allantoic or vitellinic umbilical artery, with the left umbilical vein and the right anomalous umbilical veins (three vessels).Associated with fetal anomalies such as renal agenesis, unicornuate uterus, hydranencephaly, and ipsilateral limb reduction.Type IV: one allantoic or vitellinic umbilical artery and right anomalous umbilical veins (two vessels).Associated with spontaneous miscarriage.
A single large umbilical cord artery was noted in a third of cases with VACTERL (vertebral, anal, cardiac, trachea-esophageal, renal, and limbs) association, urorectal septal malformation (URSM) sequence, OEIS (omphalocele, exstrophy of the cloaca, imperforate anus, and spinal defects) complex, half of the cases with limb body wall defect (LBWD), and in almost all the cases of sirenomelia (mermaid syndrome).In some of the few reports that had two umbilical arteries, the vessels had disproportionate sizes or one was occluded.Those entities might be a continuum of malformations in the caudal structures due to environmental or genetic factors preventing normal urorectal septum and allantois development [66].In extremely rare cases, two caudal defects may occur in the same fetus.[68].As rare as bladder agenesis is, it happens to be a common finding in the extremely rare cases of sirenomelia [66].
To consider vitelline vascular steal as the pathogenic cause of the caudal malformations, certain criteria must be met: (1) the steal artery arises above the bifurcation of the abdominal aorta; (2) the coalescence artery dominates in size over other arteries below its origin; and (3) it is present in the umbilical cord as the only or dominant artery.It is not clear yet whether vascular steal is an independent phenomenon or whether some predisposing factors can be linked as well, such as environmental factors or as a response to genetic damage of the allantois or caudal structures, and the vitelline vascular is a rescue response [66].
The lack of reports of vascular abnormalities in some reports we have reviewed might not mean the absence of actual anomalies; a lot of the cases were discovered beyond the neonatal period, and the status of the umbilical cord could not be determined, in addition to the number of patients being lost for follow-up or the family refusing autopsy.From the details in the reports, it is hard to determine if they had vitelline vascular steal without knowing the size and dominance of those vascular anomalies and their presence in the umbilical cord in a retrospective manner.
Some of the cases we have reviewed were reported to have the URSM sequence, which includes absent anal and perineal openings in association with colonic, urogenital, and lumbosacral malformations and ambiguous genitalia.It can be complete, lacking any openings, or partial, where the common cloaca is drained by a single opening with anal atresia, or urogenital, with an anus and single urogenital orifice, which is seen only in females, or lastly, an anteriorly placed anus with hypoplastic perineum [69].It is thought to be due to the incomplete subdivision of the cloaca and/or the lack of cloacal membrane breakdown [70].
From our review, we believe that possibly around 20 of the reports might have had URSM of all four subtypes but have not been identified as such (Table 5), and two fulfill the minimum diagnostic criteria of VACTERL associations, in addition to three cases where VACTERL and URSM have overlapped, and the subjects were identified with only one.
Nine cases were reported as URSM, two with sirenomelia, one VATER, and another VACTERL, in total, making up 20% of all cases.If we take into consideration the ones we have identified, it will bring the percentage to 54%.
Other pathogenic mechanisms have been raised as possible etiologies of caudal structure malformations or sequences: deficiency of the embryonic disc, deficiency of the caudal mesoderm, early amnion rupture and amniotic bands, intrauterine constraint, gene mutations, and genomic imbalance [66].
In one instance, bladder agenesis was associated with intrauterine Zika virus infection at 16 weeks of gestation, along with hypoplastic kidneys, anhydramnios, and intrauterine growth restriction [71].Calin et al. reported a case of monochorionic-diamniotic twins; the first terminated at 23 weeks of gestation with an absent bladder, urethra, vagina, anorectal atresia, omphalocele with amniotic band over limbs, and the umbilical cord; the cord was short and thin, and the second was mummified with normal internal organs [72].
Liu et al.'s studies on the effect of Adriamycin on rats resulted in bladder agenesis in 100% of rats exposed during gestational day six, compared to 83% and 77% when exposed at days seven and nine, respectively [73], stating that it was primary agenesis rather than secondary resorption of the bladder [74], and not only bladder agenesis was observed in those exposed rats but a whole spectrum of cloacal and urogenital anomalies [75].
With over half of all cases falling under the umbrella of caudal dysgenesis syndromes, one cannot ignore the fact that the other half of the cases are not yet identified as part of any syndrome or sequence, and in one case, it was isolated [53], raising the question whether there are multiple etiologies for bladder agenesis or one underlying cause resulting in highly variable anomalies.

Study limitations
While this systematic review contributes valuable insights, it is important to recognize its inherent limitations.The incorporation of case reports, while informative, inherently limits the ability to extrapolate overarching conclusions due to their retrospective and non-randomized nature.This introduces the potential for overinterpretation and biases.Furthermore, the compilation of data from diverse sources introduces a lack of standardization.Disparities become evident across crucial aspects, diagnostic procedures, and follow-up protocols.As a result, the overall robustness of the findings is moderated.
It is worth noting that these limitations provide opportunities for future research.To address the challenge of standardization, future studies could prioritize the establishment of uniform diagnostic criteria and follow-up procedures.Additionally, efforts to minimize bias could involve rigorous reporting guidelines and a more structured approach to case presentation.
Perhaps starting with identifying a common denominator will lead to an underlying cause, answering that question and aiding in mapping out the sequence.In addition to identifying its predisposing factor, this needs to be accomplished for the field to move toward a more comprehensive understanding of the rare anomaly.

Conclusions
Bladder agenesis is found to be associated with a wide spectrum of malformations, including urinary system malformations in 93% of the cases, most commonly hydronephrosis, absent, cystic, or dysplastic kidneys; and genital malformations or ambiguous genitalia in 90% of male subjects, most notably an absent phallus and penoscrotal transposition.As to the females, 70% were reported with internal or external reproduction organ abnormalities, such as ambiguous genitalia, vaginal stenosis or blind-ended, and ureteral bicornuate or agenesis, for a total of 77% of all cases; gastrointestinal anomalies in 44%, most notable being imperforated anus; musculoskeletal malformations in 38%; and cardiac malformations in 28% of the cases; similarly, 28% of all subjects had vascular abnormalities.
Only one of the reviewed cases was isolated, and on the other side of the spectrum were the ones with complex congenital anomalies who passed away within minutes of birth with pulmonary hypoplasia, the most common cause of death.Of course, the spectrum extends beyond that to reach infants who do not make it to birth.Notably, bladder agenesis was found as part of different caudal dysgenesis syndromes, such as sirenomelia, VATER/VACTERL, and urorectal septum malformation sequences.Due to the complexity of the associated congenital anomalies, bladder agenesis has a mortality rate of 38%, mostly during the first year.It has been attributed that the difference between the live births between females and males, with a ratio of 2.3:1, is due to the complexities of the associated congenital anomalies, which is reflected by the discrepancy in the mortality rates, with 74% for males and 20% for females.

FIGURE 1 :
FIGURE 1: Flowchart of database search results for reports of bladder agenesis according to the PRISMA guidelines From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.BMJ 2021;372:n71.doi: 10.1136/bmj.n71.For more information, visit http://www.prisma-statement.org/.PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
subgroup analysis and meta-regression).N/A 13f Describe any sensitivity analyses conducted to assess the robustness of the synthesized results.used to assess the risk of bias due to missing results in a synthesis (arising from reporting biases).Methodology Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.N/A

20c 1 23c 1 23d
, briefly summarize the characteristics and risk of bias among contributing studies.N/A 20b Present results of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect.Present results of all investigations of possible causes of heterogeneity among study results.N/A 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.N/A Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.N/A Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.N/A DISCUSSION 2023 Yahya et al.Cureus 15(9): e45121.DOI 10.7759/cureus.45121Discussion 23a Provide a general interpretation of the results in the context of other evidence.N/A 23b Discuss any limitations of the evidence included in the review.Limitation paragraph Discuss any limitations of the review processes used.Limitation paragraph Discuss the implications of the results for practice, policy, and future research.for the review, including the register name and registration

( 1 )
remnant cloacal type: persistent cloaca due to failure of the urorectal septum; hence, the ureters open into the remnant cloaca; (2) rectal type; (3) urogenital type: the ureter opening into the urethra or the vaginal vestibulum; (4) vaginal type; and (5) ectopic type: ureters open into the uterus.
In a case reported by Kitova et al., a fetopathological dissection of a fetus revealed mermaid syndrome with VACTERL-H syndrome: (V) myelomeningocele; (A) anal atresia; (C) cardiac defects: absent; (TE) tracheoesophageal fistula; (R) single umbilical artery; bilateral renal and ureteric agenesis; bladder agenesis; agenesis of external genitals; agenesis of the female internal gonad; (L) monkey fold of the left palm; (H) hydrocephalus

TABLE 1 : PRISMA 2020 main checklist
From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.MetaArXiv.2020, September 14.DOI: 10.31222/osf.io/v7gm2.For more information, visit www.prisma-statement.org.PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.2023 Yahya et al.Cureus 15(9): e45121.DOI 10.7759/cureus.45121Topic No. Item Reported?TITLE Title Identify the report as a systematic review.Yes BACKGROUND Objectives Provide an explicit statement of the main objective(s) or question(s) the review addresses.Present results for main outcomes, preferably indicating the number of included studies and participants for each.If meta-analysis was done, report the summary estimate and confidence/credible interval.If comparing groups, indicate the direction of the effect (i.e. which group is favored).Yes DISCUSSION Limitations of evidence Provide a brief summary of the limitations of the evidence included in the review (e.g.study risk of bias, inconsistency, and imprecision).Yes Interpretation Provide a general interpretation of the results and important implications.Yes OTHER Funding Specify the primary source of funding for the review.Yes Registration Provide the register name and registration number.No

TABLE 4 : Summary of the reports included in the review with the main anomalies, gender, and age at the time of the report
* The subject was assigned to be female according to the external genitalia; for the purposes of the statistical analysis, the biological gender was used.F: female; M: male; d: days; w: weeks; m: months; y: years; Lt: left; Rt: right; VSD: ventricular septal defect; PDA: patent ductus arteriosus; ASD: atrial septal defect; TOF: tetralogy of Fallot; VACTERL: vertebral, anal atresia, cardiac, tracheoesophageal, renal, and limbs deformities; PUJ: pelviureteric junction; DDH: developmental dysplasia of the hip; VATER: vertebral, anal, tracheoesophageal, radial, and renal anomalies.There are three types in males: (1) remnant cloacal type; (2) rectal type; and (3) urogenital sinus type.
[8]met et al. reported a case of VATER syndrome (acronym for vertebral, anal, tracheoesophageal, radial, and renal anomalies), who had a supernumerary hemivertebra with ribs and partial fusion of other ribs all 2023 Yahya et al.Cureus 15(9): e45121.DOI 10.7759/cureus.45121ontherightside; dorsolumbar scoliosis with left convexity; partial fusion of several cervical vertebrae and the sacrum; the right foot was missing two toes with syndactyly of two others (lobster claw); and a sacral caudal skin appendix, in addition to multiple anomalies affecting other systems[8].