Bladder exstrophy-epispadias complex and triple-X syndrome: incidental finding or causality?

BACKGROUND: Bladder exstrophy is a rare malformation. Prenatal diagnosis is usually an incidental finding on routine ultrasound examination. Triple-X syndrome (karyotype 47,XXX) is the most frequent sex chromosome aneuploidy in live-born females (approximately 1 in 1000). The diagnosis is often not made because women with 47,XXX karyotype have no or hardly any clinical symptoms during life. METHODS: Prenatal diagnosis of triple X karyotype is usually an incidental finding when an invasive prenatal diagnosis is performed for other reasons. RESULTS: Here, we report on two cases with bladder exstrophy and triple-X syndrome, one in a fetus and one in an adult. In view of two previous reports of this association in literature, causality of these two conditions should be considered. CONCLUSION: A gene dosage effect as possible underlying mechanisms will be discussed.

New insights into the pathogenesis of bladder exstrophy-epispadias complex.

Bladder exstrophy-epispadias complex (BEEC) is a complex and debilitating congenital disease. Familial and twin studies suggest a possible genetic component in BEEC pathogenesis. Bladder mesenchyme (detrusor) development requires induction by a signal from bladder urothelium, and we and others have shown the Shh-Gli-Bmp4 signalling pathway is likely to be involved. P63 is a master regulator in epithelial stratification and is expressed in urothelium. We have shown that p63 knock-out mice undergo excessive urothelial apoptosis. Failure of mesenchymal induction by epithelium leads to BEEC. We further demonstrated that insertion/deletion (in/del) polymorphisms (1 base pair (bp) ins and 4 bp ins., and 12 bp del) in the ΔNP63 promoter reduce transcriptional efficiency, and are associated with a statistically significant increase in the risk of BEEC in humans. Furthermore, a Genome-Wide Expression Profiling (GWEP) study suggests possible involvement of PERP in human BEEC. Intriguingly, PERP is a direct target of p63 during development, and is also involved in epithelial stratification. PERP co-localizes with desmosome, and both PERP and desmosome are essential for maintaining tissue integrity by cellular adhesion and epithelial stratification. A recent study showed that PERP and desmosome expression levels are abnormal in human BEEC patients. This review describes the role of the P63 > PERP > desmosome pathway in the development of human bladder during embryogenesis. We hypothesize that disruption of this pathway may increase the risk of BEEC.

Penile repair in patients with epispadias-exstrophy complex-can we prevent resultant hypospadias?

PURPOSE: Male genitalia reconstruction in patients with exstrophy-epispadias complex often leads to secondary hypospadias, thus requiring additional surgery and resulting in possible complications. We describe a technique of male epispadias repair to prevent resultant hypospadias. MATERIALS AND METHODS: The complete penile disassembly technique is modified by multiple Z-plasties, which enable creation of a funnel-like bladder neck and urethral plate lengthening. A total of 29 patients 2 months to 12 years old presenting with pure epispadias and bladder exstrophy were treated with this technique between 2004 and 2011. These patients were compared to 19 patients 1 day to 11 years old with exstrophy-epispadias treated with the standard penile disassembly technique between 2000 and 2004. RESULTS: Outcome measures were urethral orifice position, penile length and complications. There was no statistically significant difference between the 2 groups regarding penile length or complications. In the study group the urethra reached the tip of the glans in all patients, whereas the creation of intentional hypospadias was necessary in 6 patients (31.5%) in the control group (p <0.05). CONCLUSIONS: The modified technique was effective in obtaining appropriate meatal location without decreasing the penile length. The complication rate was not changed. Creation of resultant hypospadias at genitalia reconstruction in male epispadias should strongly be prevented.

Assisted reproductive techniques and risk of exstrophy-epispadias complex: a German case-control study.

PURPOSE: We assessed the risk of exstrophy-epispadias complex in children conceived by in vitro fertilization or intracytoplasmic sperm injection. MATERIALS AND METHODS: Data from the German Network for Congenital Uro-REctal malformations were compared to nationwide data from the German In Vitro Fertilization Register and the German Federal Statistical Office. Odds ratios (95% CI) were determined to quantify associations using logistic regression. RESULTS: A total of 123 patients with exstrophy-epispadias complex born in Germany between 1997 and 2011 were recruited through participating departments of pediatric urology and pediatric surgery throughout the country as well as the German self-help organizations Blasenekstrophie/Epispadie e.V. and Kloakenekstrophie. All German live births (10,069,986) between 1997 and 2010 comprised the controls. Overall, 12 subjects (10%) and 129,982 controls (1%) were conceived by in vitro fertilization or intracytoplasmic sperm injection. Conception by assisted reproductive technique was associated with a more than eightfold increased risk of exstrophy-epispadias complex compared to spontaneous conception (OR 8.3, 95% CI 4.6-15.0, p <0.001). Separate analyses showed a significantly increased risk of exstrophy-epispadias complex in children conceived by in vitro fertilization (OR 14.0, 95% CI 6.5-30.0, p <0.0001) or intracytoplasmic sperm injection (OR 5.3, 95% CI 2.2-12.9, p <0.0001). CONCLUSIONS: This study provides evidence that assisted reproductive techniques such as in vitro fertilization and intracytoplasmic sperm injection are associated with a markedly increased risk of having a child born with exstrophy-epispadias complex. However, it remains unclear whether this finding may be due to assisted reproduction per se and/or underlying infertility/subfertility etiology or parent characteristics.

Resultant hypospadias after epispadias repair in bladder exstrophy patients: a difficult surgical task with high complication rate.

BACKGROUND/PURPOSE: The aim of this study was to analyze the complication rate in male bladder exstrophy (BE) patients undergoing flap or graft urethroplasty for the repair of resultant hypospadias after epispadias repair. METHODS: We retrospectively reviewed the charts of 22 male BE patients who underwent 24 urethroplasties for resultant hypospadias between 2000 and 2009. Median patient age was 4.2 (range, 1.5-26.5) years, and median follow-up was 7.5 (range, 0.8-10.3) years. Meatal location after epispadias repair was midshaft in 6 cases and proximal shaft in 15. Complications were compared in relation to meatal position, type of urethroplasty (no graft vs graft), use of second-layer coverage of the urethroplasty, and use of suprapubic diversion. RESULTS: Overall, complications developed in 12 (50%) patients, including 10 urethrocutaneous fistulas and 2 urethroplasty dehiscence. Univariate analysis failed to show any differences between complicated and uncomplicated cases in all the variables. Only the 3 cases undergoing a 2-stage repair had fully successful outcomes. CONCLUSIONS: Urethroplasty in patients with BE has a high complication rate. Quality of local tissue and presence of scarring are possibly the 2 major determinants of a poor outcome. A staged repair seems the safest, although this commits the patient to 2 procedures.

Epidemiological survey of 214 families with bladder exstrophy-epispadias complex.

PURPOSE: We sought to identify causative nongenetic and genetic risk factors for the bladder exstrophy-epispadias complex. MATERIALS AND METHODS: A total of 237 families with the bladder exstrophy-epispadias complex were invited to participate in the study, and information was obtained from 214 families, mainly from European countries. RESULTS: Two families showed familial occurrence. Male predominance was found among all subgroups comprising epispadias, classic bladder exstrophy and cloacal exstrophy, with male-to-female ratios of 1.4:1, 2.8:1 and 2.0:1, respectively (p = 0.001). No association with parental age, maternal reproductive history or periconceptional maternal exposure to alcohol, drugs, chemical noxae, radiation or infections was found. However, periconceptional maternal exposure to smoking was significantly more common in patients with cloacal exstrophy than in the combined group of patients with epispadias/classic bladder exstrophy (p = 0.009). Only 16.8% of mothers followed the current recommendations of periconceptional folic acid supplementation, and 17.6% had started supplementation before 10 weeks of gestation. Interestingly, in the latter group mothers of patients with cloacal exstrophy were more compliant with folic acid supplementation than were mothers of the combined group of patients with epispadias/classic bladder exstrophy (p = 0.037). Furthermore, mothers of children with cloacal exstrophy knew significantly more often prenatally that their child would have a congenital malformation than did mothers of children with epispadias/classic bladder exstrophy (p <0.0001). CONCLUSIONS: Our study corroborates the hypothesis that epispadias, classic bladder exstrophy and cloacal exstrophy are causally related, representing a spectrum of the same developmental defect, with a small risk of recurrence within families. Embryonic exposure to maternal smoking appears to enforce the severity, whereas periconceptional folic acid supplementation does not seem to alleviate it. There is a disproportional prenatal ultrasound detection rate between severe and mild phenotypes, possibly due to the neglect of imaging of full bladders with a focus on neural tube defects.

Complete repair of bladder exstrophy in boys: can hypospadias be avoided?

INTRODUCTION: Complete repair of classic bladder exstrophy in male newborns has been successful with minimal morbidity. However, the technique may create hypospadias in some cases. We have recently adopted a modification to obtain an orthotopic meatus in bladder exstrophy boys. MATERIALS AND METHODS: Between November 1998 and December 2002 complete repair of classic bladder exstrophy was carried out in 27 boys. Complete penile disassembly was performed in 22 boys including 4 newborns and 18 older children; mean age 3+/-2 years old. Modified disassembly was used in the last 5 boys including 4 newborns and a 9-month-old boy. During repair of epispadias, the dissection starts on the ventral aspect of the penis as usual. The urethral plate is separated from both corpora cavernosa to allow ventral transposition of the plate. In the complete disassembly technique, the urethral plate is completely separated from both hemiglans. In this modification, while the urethral plate is completely separated from both corpora cavernosa, the extreme distal end of the urethral plate remains attached to the distal ends of both hemiglans. Thus, when the plate is tubularized with fine interrupted sutures the meatus ends up at the tip of the glans penis. The symphysis pubis is re-approximated as usual and corpora cavernosa are approximated dorsally in the midline. RESULTS: There was no major complication. Mean follow-up was 43+/-7 and 7+/-4 months for complete and modified disassembly groups respectively. Of the 22 boys, who underwent complete disassembly, 15 (68%) ended up with hypospadias and 7 (32%) had an orthotopic meatus. Modified disassembly has resulted in an excellent cosmetic appearance and orthotopic meatus in the 5 boys. Penile length was not shorter than boys who underwent complete disassembly. Parents of the 5 boys noticed normal straight morning erection. CONCLUSION: Although complete penile disassembly allows ventral placement of the urethra, hypospadias is created in approximately two thirds of the cases. When the extreme distal end of the urethral plate remains attached to the distal ends of both hemiglans (modified disassembly), orthotopic meatus can be obtained in all boys. With modified disassembly, posterior mobilization of the bladder and urethra does not result in corporal angulations or shortening because of the proportionate inward movement of the corpora that accompanies symphyseal approximation. The modification is feasible in newborns and infants. These short-term results may obviate the need for later penile reconstructive procedure.

In vitro fertilization and the cloacal-bladder exstrophy-epispadias complex: is there an association?

PURPOSE: The cloacal-bladder exstrophy-epispadias complex represents a collection of congenital malformations caused by failed mesenchymal development during the first trimester. We sought to determine whether the exstrophy-epispadias complex is overrepresented among children conceived by in vitro fertilization (IVF). MATERIALS AND METHODS: The clinic charts of all patients born between 1998 and 2001 who presented to our institution with the exstrophy-epispadias complex were reviewed. Four patients conceived by IVF and born with exstrophy-epispadias were identified and telephone interviews were conducted with the parents. Statistical analysis using clinical data and available United States population data was performed. RESULTS: Of 78 clinic patients with exstrophy-epispadias born during a 4-year period 4 were conceived using IVF. An estimated 12% to 14% of children born in the United States with the exstrophy-epispadias complex are evaluated annually at our institution. During the years 1997 to 2000, 112,137 children in the United States were conceived using IVF. According to published incidence data, approximately 5 children with exstrophy-epispadias would be expected among this entire population. Expected numbers of children in the United States conceived by IVF and born with exstrophy-epispadias during a 4-year period were calculated based on the observed number in our clinic population. A resulting 7.3-fold relative increase in incidence was determined (p = 0.0021). CONCLUSIONS: The exstrophy-epispadias complex appears to occur more frequently in children conceived by in vitro fertilization.

[Results of bladder and urethra reconstruction for exstrophy]. / Résultats de la reconstruction vésicale et urétrale pour exstrophie.

Sixty-one patients with classical bladder exstrophy were seen at our institution over the last twenty-two-years. Five patients underwent primary urinary diversion, in six reconstruction according Couvelaire--Arap method was attempted without success. For fifty patients a staged approach to functional closure was elected. A review of the success, failures and complications provides the bases for treatment now being used on new patients. The technical aspects of this treatment that provide the best chance for continence without renal damage and satisfactory external genitalia are discussed. An excellent surgical result, defined as achievement of a day time dry interval for 3 hours with normal social life and without renal damage was achieved in 74% of children (100% of girls).

Female epispadias: report of a case and review of the literature.

Female epispadias is a congenital anomaly representing a mild form of the spectrum of exstrophy of the bladder. Unrecognized an untreated, the handicap associated with the physical malformation can create overwhelming clinical and psychological problems for the affected female. Radiographic findings of spinal dysrhaphism with diastasis of the public bones are often associated with, and can afford the first clue to, the physical findings of absent clitoris, ununited labia and patulous and foreshortned urethra.