Effect of failed initial closure on bladder growth in children with bladder exstrophy.

PURPOSE: Failed initial bladder exstrophy closure may hinder the natural course of bladder growth compared to successful primary reconstruction. By measuring successive bladder capacities within the first 5 years of life, we compared the rate of bladder growth in children with failed vs successful initial closure. MATERIALS AND METHODS: We used an approved bladder exstrophy database to identify and review retrospectively patients with classic bladder exstrophy who underwent repeat cystograms between ages 1 and 6 years. Two groups of patients were identified--those with successful neonatal closure (group 1) and those with successful reclosure after an initial failed procedure (group 2). A generalized linear mixed model was fit to evaluate the impact of treatment group and age on bladder growth. RESULTS: We identified 48 patients in group 1 (75% male) and 62 in group 2 (71% male). Initial pelvic osteotomy was done in 60% of group 1 and 34% of group 2. Patients in group 1 had significantly larger cystographic capacity at 2, 4, 5 and 6 years after successful bladder closure compared to those in group 2 (p <0.05). The bladder tended to grow at a significantly slower rate in group 2 (9.38 cc yearly) compared to group 1 (14.76 cc yearly, p = 0.005). CONCLUSIONS: Patients with initial failed bladder exstrophy closure showed significantly smaller cystographic capacities and slower bladder growth compared to those who underwent successful neonatal bladder closure. These data clearly underscore the importance of a secure, successful primary closure.

Complete primary repair of bladder exstrophy: a systematic review.

OBJECTIVES: Complete primary repair of exstrophy (CPRE) was established as a method to reduce numbers of procedures for the reconstruction of bladder exstrophy (BE). Performed since 1989, some suggest it as a replacement for the staged reconstructive procedure, the gold standard. Does CPRE reduce the numbers of procedures for reconstruction of BE? METHODS: Literature was reviewed from 1989 to 2016, and articles evaluating outcomes of patients undergoing CPRE, extracted. Effort was made to obtain final data from each reporting institution/group. Eleven articles meeting criteria were evaluated for qualitative systematic review. Age at initial closure, complications, additional procedures, and outcomes were evaluated to provide an overview of CPRE. RESULTS: Ten groups reported BE management using the CPRE technique. 236 patients (153 boys; 72 girls; 11 unknown sex) had primary closure ranging from birth to 5.6 years. Osteotomy was favored by most in infants closed beyond the first 72 h of life along with spica cast immobilization. Three groups recommended concomitant augmentation for infants with small bladder capacities. Ureteral reimplantation was required in 58 patients with recurrent urinary tract infections resistant to prophylaxis. Hypospadias repair was required for most boys having complete penile disassembly, and most children eventually required bladder neck reconstruction (BNR) for continence. Overall, voiding without BNR was noted in 16-37% of children in the reported series. CONCLUSIONS: Complete primary repair of exstrophy has been suggested as a single procedure for the management of BE. Literature review suggests most patients require multiple procedures to complete reconstruction and attain continence.

Bladder neck transection for intractable pediatric urinary incontinence.

PURPOSE: We report the indications, technique and outcome of a large series of children who underwent bladder neck transection for intractable urinary incontinence. MATERIALS AND METHODS: We retrospectively reviewed demographics, operative details, complications and outcomes of 76 patients (47 males, 29 females) who underwent bladder neck closure at our institution between 1996 and 2006. Mean patient age at the time of the procedure was 12 years, 10 months. The most common diagnosis was bladder exstrophy. Of the patients 31 had undergone prior bladder neck reconstruction (30) or sling repair (1). All patients underwent concomitant augmentation and creation of a catheterizable stoma. RESULTS: A total of 50 patients had more than 12 months of followup (mean 44, range 12 to 128). Continence was achieved initially in 86% of the patients (43 of 50). Of the 7 primary failures 2 leaked via the urethra and 5 via the stoma. Six of these patients achieved dryness with revision, for a final continence rate of 98%. A single renal unit suffered significant loss of function during this period. New, nonobstructive hydronephrosis developed in 8 additional renal units. Stones developed in 30% of the patients. There were no spontaneous bladder ruptures. CONCLUSIONS: Bladder neck transection in combination with enterocystoplasty and creation of a continent catheterizable stoma is an effective approach to incontinent cases with severely damaged bladder outlets and poor quality bladders in which other reconstructive approaches either have failed or are deemed likely to fail. Specific concerns regarding the risk of poor renal outcomes and perforation seem unwarranted at present.

Complications of complex lower urinary tract reconstruction in patients with neurogenic versus nonneurogenic bladder--is there a difference?

PURPOSE: The complications of lower urinary tract reconstruction have been well documented in children with neurogenic bladders. While most series include small numbers of nonneurogenic diagnoses, this group is typically underrepresented. Despite a number of fundamental anatomical and functional differences, a direct comparison of surgical complications of lower urinary tract reconstruction in patients with neurogenic vs nonneurogenic bladders has not been performed. MATERIALS AND METHODS: We identified patients undergoing lower urinary tract reconstruction incorporating enterocystoplasty from 1996 to 2006. We performed a retrospective review of operative notes and medical records of patients who met inclusion criteria. Patients were divided into a neurogenic group and a nonneurogenic group based on the underlying diagnosis. The 2 groups were compared with respect to demographics, historical data, operative techniques, perioperative morbidity, long-term complications and need for surgical revision. RESULTS: Of the 127 patients who met inclusion criteria 72 were assigned to the nonneurogenic group and 55 to the neurogenic group. Overall the rates of significant perioperative morbidity (39%), long-term complications (54%) and need for surgical revision (39%) were substantial. The rates of catheter related complications, rehospitalization for dehydration and spontaneous bladder rupture were higher in the neurogenic group (p <0.05). CONCLUSIONS: Reconstruction of the lower urinary tract in children is associated with a considerable rate of complications and need for surgical revision regardless of whether the bladder is neurogenic or nonneurogenic. Children with neurogenic bladders are more prone to spontaneous rupture, catheter mishaps and early rehospitalization for dehydration.

Reliability of grading of vesicoureteral reflux and other findings on voiding cystourethrography.

INTRODUCTION: Voiding cystourethrography (VCUG) is the modality of choice to diagnose vesicoureteral reflux (VUR). Although grading of VUR is essential for prognosis and clinical decision-making, the inter-observer reliability for grading has been shown to vary substantially. The Randomized Intervention for Children with VesicoUreteral Reflux (RIVUR) trial provides a large cohort of children with VUR to better understand the reliability of VCUG findings. OBJECTIVE: To determine the inter-observer consistency of the grade of VUR and other VCUG findings in a large cohort of children with VUR. STUDY DESIGN: The RIVUR trial is a randomized controlled trial of antimicrobial prophylaxis in children with VUR diagnosed after UTI. Each enrollment VCUG was read by a local clinical (i.e. non-reference) radiologist, and independently by two blinded RIVUR reference radiologists. Reference radiologists' disagreements were adjudicated for trial purposes. The grade of VUR and other VCUG findings were extracted from the local clinical radiologist's report. The unit of analysis included individual ureters and individual participants. We compared the three interpretations for grading of VUR and other VCUG findings to determine the inter-observer reliability. RESULTS: Six-hundred and two non-reference radiology reports from 90 institutions were reviewed and yielded the grade of VUR for 560 left and 524 right ureters. All three radiologists agreed on VUR grade in only 59% of ureters; two of three agreed on 39% of ureters; and all three disagreed on 2% of ureters (Table). Agreement was better (≥92%) for other VCUG findings (e.g. bladder shape "normal"). The non-reference radiologists' grade of VUR differed from the reference radiologists' adjudicated grade by exactly one grade level in 19% of ureters, and by two or more grade levels in 2.2% of ureters. When the participant was the unit of analysis, all three radiologists agreed on the grade of VUR in both ureters in just 43% of cases. DISCUSSION: Our study shows considerable and clinically relevant variability in grading VUR by VCUG. This variability was consistent when comparing non-reference to the adjudicated reference radiologists' assessment and the reference radiologists to each other. This study was limited to children with a history of UTI and grade I-IV VUR and may not be generalizable to all children who have a VCUG. CONCLUSION: The considerable inter-observer variability in VUR grading has both research and clinical implications, as study design, risk stratification, and clinical decision-making rely heavily on grades of VUR.

Variation in the level of detail in pediatric voiding cystourethrogram reports.

INTRODUCTION: Voiding cystourethrogram (VCUG) provides a wealth of data on urinary tract function and anatomy, but few standards exist for reporting VCUG findings. OBJECTIVE: We aimed to assess variability in VCUG reports and to test our hypothesis that VCUG reports from pediatric facilities and pediatric radiologists are more complete than those performed at other facilities or by non-pediatric radiologists. STUDY DESIGN: We analyzed original VCUG reports from children enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial. A 23-item checklist was created and used to evaluate reporting of technical (e.g. catheter size), anatomic (e.g. vesicoureteral reflux (VUR) presence and grade, bladder shape), and functional information (e.g. bladder emptying). Radiologists were classified as pediatric or non-pediatric radiologists. Facilities were categorized as to whether they were a free-standing pediatric hospital (FSPH), a pediatric "hospital within a hospital" (PHWH), a non-pediatric hospital (NPH), or an outpatient radiology facility (ORF). Multivariate linear regression was used to analyze factors associated with the completeness of the VCUG reports (percent of items reported from the 23-item checklist). RESULTS: Six-hundred and two VCUGs were performed at 90 institutions. Of those, 76% were read by a pediatric radiologist, and 49% were performed at a FSPH (Table). On average, less than half of the 23 items in our standardized assessment tool were included in VCUG reports (mean 48%, SD 12). The completeness of reports varied by facility type: 51% complete at FSPH (SD 11), 50% at PHWH (SD 10), 36% at NPH (SD 11), and 43% at ORF (SD 8) (p < 0.0001). In multivariate analysis, VCUG reports generated at NPH or ORF had 8% fewer items included (95% CI 3.0-12.8, p < 0.01), and those generated at PHWH did not differ from those generated at FSPH. Reports read by a non-pediatric radiologist had 6% fewer items included (95% CI 3-9.7; p < 0.01) compared with those read by a pediatric radiologist. DISCUSSION: There is substantial underreporting of findings in VCUG reports when assessing a widely represented sample of routine, community-generated reports using an idealized standard. Although VUR was often reported, other crucial anatomic and functional findings of the VCUG were consistently underreported across all facility types. CONCLUSION: Although pediatric radiologist and pediatric hospitals generated more complete VCUG reports compared with those having non-pediatric origins, the differences are small when considering the substantial underreporting of VCUG findings in general. This underscores the opportunities for improvement in reporting of VCUG findings.

Preservation of renal function in the modern staged repair of classic bladder exstrophy.

OBJECTIVE: To compare the estimated glomerular filtration rate (eGFR) in bladder exstrophy patients with published normative GFR estimates. PATIENTS AND METHODS: eGFR was calculated using the Schwartz formula at three timepoints, with mean eGFR at each timepoint compared to normative values. RESULTS: At primary closure (n = 53) the mean eGFR (ml/min/1.73 m(2)) in exstrophy patients was similar to norms at 0-7 days (exstrophy vs norm: 42.5 vs 40.6, p > 0.05) and after 2 years of age (108.8 vs 133, p > 0.05). However, the mean eGFR in exstrophy patients was significantly lower than norms between 8 days (44.8 vs 65.8, p < 0.0001) and 2 years of life (68 vs 95.7, p = 0.01). At bladder neck reconstruction (n = 13) no statistically significant difference existed between the exstrophy and normative eGFR values (137.1 vs 133, p > 0.05). Similarly, among 27 patients with at least 1 year follow-up after bladder neck reconstruction, the mean exstrophy eGFR was no worse or higher than normative values (2-12 years: 124.5 vs 133, p > 0.05; males ≥13 years 175.6 vs 140, p = 0.04; females ≥13 years 128.8 vs 126, p > 0.05). CONCLUSION: The staged reconstruction of exstrophy does not appear to negatively impact renal function in most patients. As eGFR detects only significant changes, surgical reconstruction may still cause more subtle renal damage.

Urological outcomes in the omphalocele exstrophy imperforate anus spinal defects (OEIS) complex: experience with 80 patients.

OBJECTIVE: To review the urological management and outcomes of patients with the OEIS (omphalocele, exstrophy of the bladder, imperforate anus, spinal abnormalities) complex. PATIENTS AND METHODS: 80 patients with the OEIS complex managed at a single institution between 1974 and 2009 were reviewed. RESULTS: 37 had initial closure at our institution (2 failed - 5%); 22 with successful closure were referred for incontinence; 15 failed closure at an outside institution (2 of whom are awaiting closure); 6 are skin-covered variants. Osteotomy was performed in 39/43 (91%) with successful closure versus 8/17 (47%) who failed initial bladder closure. 40 were dry (56%), but most needed additional urinary reconstruction: 2 had small bowel neobladders; 32 (84%) had augmentation cystoplasty; 30 (79%) had a continent catheterizable channel; only 9 (24%) were continent with an intact urethra. Bladder neck reconstruction allowed dryness in 7 (18%). 45 patients had XY genotype--19 had female gender assignment at birth. All patients with XX genotype had female gender assignment. CONCLUSIONS: Osteotomy improves success of initial bladder closure. A bladder neck procedure, catheterizable channel, and augmentation cystoplasty will be required in the majority of patients to attain urinary dryness.

Delayed primary closure of bladder exstrophy: immediate postoperative management leading to successful outcomes.

OBJECTIVE: To present the critical features of our postoperative plan for children undergoing delayed primary bladder closure because appropriate postoperative management is crucial to successful exstrophy repair. METHODS: Using an institutionally approved database, patients with bladder exstrophy whose primary bladder closure was performed at least 1 month after birth were identified. All aspects of the postoperative management were reviewed. RESULTS: A total of 20 patients (18 boys) were identified: 19 with classic bladder extrosphy and 1 with an exstrophy variant. The patients underwent closure at a mean age of 9.9 months. All patients underwent pelvic osteotomy and immobilization for an average of 34.8 days. Analgesia was administered by way of a tunneled epidural catheter in 90% of patients for an average of 18.8 days, and 12 patients (60%) required adjunct intravenous analgesia. Bilateral ureteral catheters and suprapubic tubes were used in all patients. Total parenteral nutrition was administered to 10 (83%) of 12 patients who underwent closure after 2000. All patients received preoperative antibiotics and 2 weeks of postoperative intravenous antibiotics that was followed by oral prophylaxis. The mean hospital stay was 6.3 weeks. With an average follow-up of 7.4 years, delayed closure was 100% successful. CONCLUSION: Successful delayed primary closure of bladder exstrophy requires a multidisciplinary approach. The keys to success include osteotomy, pelvic immobilization, analgesia, nutritional support, maximal bladder drainage, and infection prophylaxis.

Medical comorbidities associated with pediatric kidney stone disease.

OBJECTIVES: To characterize the relationship between pediatric kidney stone disease and the presence of hypertension (HTN), diabetes mellitus (DM), and obesity. In adults, kidney stone disease has been associated with medical comorbidities such as HTN, DM, and obesity. Similar analyses have never been performed for the pediatric population. METHODS: The 2003 and 2006 Kids' Inpatient Databases were queried to identify subjects treated for kidney stone disease ("International Classification of Diseases" codes 9592.0 and 592.1). The comorbidities of HTN, DM, and obesity were identified using the provided comorbidity software. The risk of kidney stone disease associated with age, sex, and comorbidity status was evaluated using multivariate logistic regression. RESULTS: A total of 6,115,443 subjects were evaluated. Of these, 14,245 (0.2%) had a diagnosis of upper tract calculus (4092 boys and 10,045 girls, sex unavailable for 108). Age was the strongest independent predictor of stone risk (P < .0001). HTN was associated with a significantly increased risk of stone diagnosis in children ≤10 years old and DM for children ≤5 years old. Stone risk was not affected by obesity in any age group. CONCLUSIONS: The results of our study have shown that kidney stone disease is significantly associated with age among all children and both HTN and DM for young children. Although exploratory, these findings are novel and suggest that kidney stone disease among young children might be associated with nonrenal, systemic disease states.

Operative management of pediatric urolithiasis.

Surgical management of urinary stones in children remains challenging due to the smaller caliber of the urinary tract. Specific instruments have been designed to overcome some of the issues related to pediatric stone management. Endoscopic and percutaneous modalities for stone management have been shown to be as safe and effective in providing stone clearance in children as in adults. Technologies that have been shown to be safe in adults are being miniaturized for use in children. The current literature regarding pediatric urolithiasis was reviewed in an effort to identify trends in operative management. Additionally, techniques used successfully at our institution are described. Although not an exhaustive review of all available modalities and instruments, this review will provide an overview of the current techniques for the management of pediatric urolithiasis.

Vaginoplasty in the female exstrophy population: Outcomes and complications.

OBJECTIVE: Vaginal stenosis is a common sequela in adolescents who have undergone reconstruction for classic bladder exstrophy in infancy. We sought to determine the incidence of vaginal stenosis in our patient population and the outcome of treatment in the first three decades of life. PATIENTS AND METHODS: An institutional review board approved bladder exstrophy database was used to identify and retrospectively review classic female bladder exstrophy patients aged 12-30 years treated at the authors' institution. Patients who underwent vaginoplasty were identified and the following outcomes were measured: age at surgery, method used for the reconstruction, complications and incidence of re-stenosis. RESULTS: Ninety-one female classic bladder exstrophy patients were identified. Twenty-nine patients (31.8%) underwent vaginoplasty because of vaginal stenosis at a mean (SD) age of 15 (3) years. Twenty-four patients underwent perineal flap vaginoplasty, three posterior cut-back vaginoplasty and two YV vaginoplasty. One patient developed wound infection and dehiscence which required reoperation (3.4%). No patient experienced vaginal re-stenosis. CONCLUSIONS: vaginal stenosis is common after reconstruction of female classic bladder exstrophy. Vaginoplasty is highly successful in the exstrophy population when performed in the second or third decade of life with a low risk of complications.

Perioperative anesthetic and analgesic management of newborn bladder exstrophy repair.

OBJECTIVE: Reconstruction of bladder exstrophy in newborn infants requires immobilization, sedation and pain management to prevent distracting forces from compromising the repair. We present a 6-year review of our experience. SUBJECTS AND METHODS: We reviewed the perioperative management of newborn infants undergoing reconstruction between November 1999 and October 2006. Data are presented as means+/-SD. RESULTS: Twenty-three newborn infants underwent surgery under a combined epidural and general anesthetic technique. Tunneled caudal epidural catheters were inserted in all patients and intermittently injected with 0.25% bupivacaine with 1:200,000 epinephrine. Postoperatively, a continuous infusion of 0.1% lidocaine, 0.8-1mg/kg/h was administered for 15+/-8 (range 4-30) days. Children were sedated with diazepam for 20+/-13 (range 2-40) days. Central venous catheters were maintained for 20+/-9 (range 1-34) days for fluids, drug administration and blood sampling. No patient experienced bladder prolapse or wound dehiscence. CONCLUSION: Perioperative management with tunneled epidural and central venous catheters in newborn infants with bladder exstrophy facilitates immobilization, analgesia and sedation, resulting in an excellent cosmetic repair with no case of bladder prolapse or wound dehiscence.

Outcomes of delayed hypospadias repair: implications for decision making.

PURPOSE: The current American Academy of Pediatrics recommendation is to perform hypospadias repair at age 6 to 12 months. Primary hypospadias repair at adolescence or beyond is uncommon, and there is little reported about the postoperative course of such patients. We report the outcomes for a series of patients who underwent primary hypospadias repair at age 10 years or older. MATERIALS AND METHODS: We identified patients seen at our institution between 1979 and 2002 who underwent primary hypospadias repair at age 10 years or older. Electronic and paper charts were abstracted for baseline demographics, degree of hypospadias, surgical technique, complications and reoperation. RESULTS: A total of 31 patients were identified, with a median available followup of 14 months. Median patient age at first hypospadias surgery was 13 years. The location of the urethral meatus was distal in 19 patients, mid shaft in 7, proximal in 4 and undetermined in 1. A variety of techniques were used, including meatal advancement and glanuloplasty, meatal based flaps, island onlay flaps, Snodgrass repair and staged procedures. Complications were noted in 48% of patients (15 of 31), including fistula (10), stricture (4), hematoma (2) and other complications (2). CONCLUSIONS: Although retrospective in nature, these data suggest that delay of primary hypospadias repair into the teen years or beyond may result in more complications than currently accepted for infant hypospadias repair.

Subspecialty training and surgical outcomes in children with failed bladder exstrophy closure.

OBJECTIVES: Failure of initial and subsequent bladder closures has significant implications for patients with bladder exstrophy. We evaluated the association between outcomes of repeat bladder closure among patients who failed initial closure, and the credentials and training of the operating surgeons. MATERIALS AND METHODS: From a bladder exstrophy database, we identified patients with a failed initial exstrophy repair. Records were evaluated with respect to success of the bladder closure (dehiscence or prolapse), number of closures required, surgeon credentials (fellowship-trained pediatric urologists (FPU) or other surgeons (OS)), post-closure bladder capacity, subsequent continence procedures, and continence outcomes. RESULTS: Of 101 patients whose initial bladder closure failed, 94 patients underwent repeat bladder closure, of which 65 (69%) were successful. Of repeat closures performed by FPUs, 84% (54/64) were successful, while only 37% (10/28) of repeat closures performed by OSs were successful (P<0.0001). Of the 65 patients whose repeat bladder closure was successful, 38 (58%) achieved bladder capacity adequate for bladder neck reconstruction (BNR), versus only 10/29 (34%) patients whose repeat closure failed (P=0.032). Overall, after repeat closure, 26% were completely dry after BNR, 41% were partially dry after BNR, and 33% required further reconstruction for continence. CONCLUSIONS: Among bladder exstrophy patients who fail their initial closure, repeat closure is more successful when the surgeon is a fellowship-trained pediatric urologist, and failure of repeat closure bodes ill for long-term continence. Exstrophy outcomes may be better at centers of excellence with significant experience in the management of this rare, complex condition.

Time to recurrent stone formation in patients with bladder or continent reservoir reconstruction: fragmentation versus intact extraction.

PURPOSE: Stone formation following bladder or continent reservoir reconstruction in children is a major source of long-term morbidity. We determine whether the method of stone removal (fragmentation or intact extraction) affected the time to stone recurrence in children after bladder reconstruction. MATERIALS AND METHODS: Medical records from 1993 to 2003 were examined to identify patients with urinary reconstruction subsequently treated for bladder calculi at our institution. Retrospective review of the medical records was performed to determine the type of urinary reconstruction, time to stone recurrence, method of stone removal and length of followup. Kaplan-Meier analysis was performed with each stone episode considered as an individual event. Time to recurrence was measured in months from stone removal to identification of recurrent stones. RESULTS: A total of 60 patients with bladder or continent reservoir reconstructions had undergone 103 stone removal procedures (range 1 to 8 procedures per patient). Patients were rendered stone-free after each procedure. Stones recurred following 42.4% of intact and 43.9% of fragmented extractions at a mean of 27.0 (SD 31.3) and 27.6 (SD 21.8) months, respectively. Kaplan-Meier survival analysis curves for intact and fragmented extractions were not statistically different. CONCLUSIONS: Time to stone recurrence in patients with bladder or continent reservoir reconstruction is not altered by the method of stone removal (fragmented versus intact extraction). Since recurrence remains a frequent problem in children after bladder augmentation and/or reconstruction, use of the least invasive modality should be the initial management recommendation.

High-grade renal injuries in children--is conservative management possible?

OBJECTIVES: To review our experience with the management of high-grade (grade IV and V) renal injuries to clarify the role of conservative management. METHODS: From 1991 to 2003, 79 consecutive patients (age range 2 to 14 years) with renal injuries were treated in an urban level I pediatric trauma center. Twenty children were identified as having high-grade renal injury (grade IV, 10 children and grade V, 10 children). The mechanism of injury was blunt trauma in 17 patients (85%) and penetrating trauma in 3 (15%). RESULTS: Of the 10 patients with grade IV injury, 8 (80%) were successfully treated conservatively with bedrest and catheter drainage. Two patients with persistent urine leaks required ureteral stenting, and one subsequently required open operative repair. The initial radiographic findings in both patients demonstrated complete renal fracture with retained vasculature to both renal segments. All 10 patients with grade V injury required open operative management and only 3 (30%) achieved long-term renal salvage. CONCLUSIONS: Most children with grade IV renal injury can be treated conservatively. Patients with complete renal fracture or significant urinary extravasation on initial radiographic imaging may be less likely to undergo spontaneous resolution. Patients with a persistent urinary leak can be successfully treated with internal drainage. Grade V injuries are associated with an increased risk of requiring open operative intervention, and the renal preservation rates are low.

Clinical and molecular characterization of the bladder exstrophy-epispadias complex: analysis of 232 families.

OBJECTIVE: To identify genetic and nongenetic factors contributing to the risk of bladder exstrophy-epispadias complex (BEEC). PATIENTS AND METHODS: In all, 285 families with BEEC were invited to participate in the study, and 232 of them were recruited. Epidemiological information was obtained from 151 of the consenting families, with a detailed clinical genetic examination of 94 probands. In all, 440 DNA samples were collected from 163 families for molecular analysis. RESULTS: Most of the cases were sporadic and had no family history of BEEC. Among patients, 95% were Caucasian, and males were more common in both the epispadias group (M/F, 2.2, 29 patients) and the classic bladder-exstrophy group (M/F 1.8, 164), but in the cloacal exstrophy group the sex ratio was close to unity (1.1, 15). There was a statistically significant association with advanced parental age (P < 0.001). Birth weight, gestational age and maternal reproductive history did not appear to be significantly different from those in the general population. Information on exposures to tobacco, alcohol and drugs was collected but none appeared to act as a risk factor. Karyotype analysis on 37 cases detected two chromosomal abnormalities, i.e. 46XY t(8;9)(p11.2; q13) and 47XYY. Molecular analysis of the HLXB9 gene, which causes Currarino syndrome, did not detect mutations in the blood or bladder DNA of 10 patients with bladder or cloacal exstrophy. CONCLUSIONS: BEEC most commonly occurs as an isolated sporadic birth defect with a recurrence risk of << 1%. There was no evidence of a single-gene effect or common environmental factor in this study population. In addition to race and advanced parental age, birth order may be a risk factor for BEEC. We suggest somatic mutations in a gene(s) within the pathway regulating bladder development may be the cause of BEEC.