Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene.

BACKGROUND: Prune belly syndrome (PBS) is a rare, multi-system congenital myopathy primarily affecting males that is poorly described genetically. Phenotypically, its morbidity spans from mild to lethal, however, all isolated PBS cases manifest three cardinal pathological features: 1) wrinkled flaccid ventral abdominal wall with skeletal muscle deficiency, 2) urinary tract dilation with poorly contractile smooth muscle, and 3) intra-abdominal undescended testes. Despite evidence for a genetic basis, previously reported PBS autosomal candidate genes only account for one consanguineous family and single cases. METHODS: We performed whole exome sequencing (WES) of two maternal adult half-brothers with syndromic PBS (PBS + Otopalatodigital spectrum disorder [OPDSD]) and two unrelated sporadic individuals with isolated PBS and further functionally validated the identified mutations. RESULTS: We identified three unreported hemizygous missense point mutations in the X-chromosome gene Filamin A (FLNA) (c.4952 C > T (p.A1448V), c.6727C > T (p.C2160R), c.5966 G > A (p.G2236E)) in two related cases and two unrelated sporadic individuals. Two of the three PBS mutations map to the highly regulatory, stretch-sensing Ig19-21 region of FLNA and enhance binding to intracellular tails of the transmembrane receptor ß-integrin 1 (ITGß1). CONCLUSIONS: FLNA is a regulatory actin-crosslinking protein that functions in smooth muscle cells as a mechanosensing molecular scaffold, transmitting force signals from the actin-myosin motor units and cytoskeleton via binding partners to the extracellular matrix. This is the first evidence for an X-linked cause of PBS in multiple unrelated individuals and expands the phenotypic spectrum associated with FLNA in males surviving even into adulthood.

Phenotypic severity scoring system and categorisation for prune belly syndrome: application to a pilot cohort of 50 living patients.

OBJECTIVE: To design a novel system of scoring prune belly syndrome (PBS) phenotypic severity at any presenting age and apply it to a large pilot cohort. PATIENTS AND METHODS: From 2000 to 2017, patients with PBS were recruited to our prospective PBS study and medical records were cross-sectionally analysed, generating individualised RUBACE scores. We designed the pragmatic RUBACE-scoring system based on six sub-scores (R: renal, U: ureter, B: bladder/outlet, A: abdominal wall, C: cryptorchidism, E: extra-genitourinary, generating the acronym RUBACE), yielding a potential summed score of 0-31. The 'E' score was used to segregate syndromic PBS and PBS-plus variants. The cohort was scored per classic Woodard criteria and RUBACE scores compared to Woodard category. RESULTS: In all, 48 males and two females had a mean (range) RUBACE score of 13.8 (8-25) at a mean age of 7.3 years. Segregated by phenotypic categories, there were 39 isolated PBS (76%), six syndromic PBS (12%) and five PBS-plus (10%) cases. The mean RUBACE scores for Woodard categories 1, 2, and 3 were 20.5 (eight patients), 13.8 (25), and 10.6 (17), respectively (P < 0.001). CONCLUSIONS: RUBACE is a practical, organ/system level, phenotyping tool designed to grade PBS severity and categorise patients into isolated PBS, syndromic PBS, and PBS-plus groups. This standardised system will facilitate genotype-phenotype correlations and future prospective multicentre studies assessing medical and surgical treatment outcomes.

Cost comparison of intra-detrusor injection of botulinum toxin versus augmentation cystoplasty for refractory neurogenic detrusor overactivity in children.

INTRODUCTION: Treatment options for refractory neurogenic detrusor overactivity (NDO) in children include botulinum toxin type A (BTX-A) and augmentation cystoplasty (AC). Although BTX-A is accepted in contemporary pediatric urologic practice, cost and long-term outcomes data for BTX-A are limited relative to the gold standard, AC. The purpose of this study was to compare the projected 10-year costs of AC versus BTX-A. METHODS: We performed a cost analysis from the payer perspective by computationally modeling treatment sequences by a Markov model. In the model, we used probabilities derived from published sources, and costs obtained at a tertiary medical center. The base case was a pediatric patient with refractory NDO. In the model, we assumed biannual BTX-A treatments. Treatment costs over 10 years were compared between immediate AC versus bridging therapy with BTX-A. Using the computational model, we simulated 100,000 instances of 10-year treatment cost for each of the two treatment modalities. The costs for the two treatment approaches were then compared using t-test and Wilcoxon test. RESULTS: The projected median and mean 10-year cost of immediately AC were $51,798.72 (95% CI [$51,798.72, $327,483.80]) and $123,473.4 (SD: $98,085.23) respectfully, while the projected median and mean 10-year cost of bridging therapy with BTX-A prior to proceeding to AC as needed were $74,552.46 (95% CI [$53,188.56, $309,913.07]) and $124,858.80 (SD: $84,495.35) (p < 0.001). CONCLUSIONS: For a typical index pediatric patient with NDO, bridging therapy with intravesical BTX-A is associated with an increased cost compared to immediate AC over a ten-year period.

Design and validation of a low-cost, high-fidelity model for robotic pyeloplasty simulation training.

INTRODUCTION/BACKGROUND: Owing to restrictions in operative experiences, urology residents can no longer solely rely on 'hands-on' operative time to master their surgical skills by the end of residency. Simulation training could help residents master basic surgical skills and steps of a procedure to maximize time in the operative room. However, simulators can be expensive or tedious to set up, limiting the availability to residents and training programs. OBJECTIVE: The authors sought to develop and validate an inexpensive, high-fidelity training model for robotic pyeloplasty. STUDY DESIGN: Pyeloplasty models were created using Dragon Skin® FX-Pro tissue-mimicking silicone cast over 3-dimensional molds. Urology faculty and trainees completed a demographic questionnaire. The participants viewed a brief instructional video and then independently performed robotic dismembered pyeloplasty on the model. Acceptability and content validity were evaluated via post-task evaluation of the model. Construct validity was evaluated by comparing procedure completion time, the Global Evaluative Assessment of Robotic Skills (GEARS) score, blinded subjective physical evaluation of repair quality (1-10 scale), and flow rate between experts and novices. RESULTS: In total, 5 urology faculty, 6 fellows, and 14 residents participated. The median robotic console experience among faculty, fellows, and residents was 8 years (interquartile range [IQR] = 6-11), 3.5 years (IQR = 2-4 years), and 0 years (IQR = 0-0.5 years), respectively. The median procedure completion time was 29 min (IQR = 26-40 min), and the median flow rate was 1.11 mL/s (IQR = 0-1.34 mL/s). All faculty had flow rates >1.25 mL/s and procedure times <30 min compared with 2 of 6 fellows and none of the residents (P < 0.001). All faculty, half of the fellows, and none of the residents achieved a GEARS score ≥20, with a median resident score of 12.5 (IQR = 8-13) (P < 0.001). For repair quality, all faculty scored ≥9 (out of 10), all fellows scored ≥8, and the median score among residents was 6 (IQR = 2-6) (P < 0.001). The material cost was $1.32/model, and the average production time was 0.12 person-hours/model. DISCUSSION AND CONCLUSION: This low-cost pyeloplasty model exhibits acceptability and content validity. Construct validity is supported by significant correlation between participant expertise and simulator performance across multiple assessment domains. The model has excellent potential to be used as a training tool in urology and allows for repetitive practice of pyeloplasty skills before live cases.

Streamlining risk stratification in infants and young children with spinal dysraphism: Vesicoureteral reflux and/or bladder trabeculations outperforms other urodynamic findings for predicting adverse outcomes.

BACKGROUND: Baseline and interval dimercaptosuccinic acid (DMSA) scans and urodynamic (UD) studies are often obtained in infants and young children with spinal dysraphism (SD). OBJECTIVE: To identify practical UD parameters which accurately stratify urologic risk young children with SD. STUDY DESIGN: 130 expectantly managed infants/young children with SD and initial DMSA and UD before age 2 were reviewed. End fill pressure (EFP), bladder trabeculations, vesicoureteral reflux (VUR), initial volume (IV) drained at UD catheter placement, and detrusor pressure at initial volume (DPIV) were evaluated for association with subsequent febrile urinary tract infection (UTI), DMSA abnormalities, and early clean intermittent catheterization (CIC). A combination of factors to accurately stratify risk was sought. Groups were compared by log-rank test. The association of CIC and febrile UTI incidence was evaluated. RESULTS: 31/130 patients developed DMSA abnormalities, 52/130 started early CIC, and 61/130 developed a febrile UTI with median follow-up of 3.8 years. Trabeculations, VUR, EFP ≥40 cm H2O, IV ≥50% estimated bladder capacity (EBC), and DPIV >10 cm H2O were associated with subsequent abnormal DMSA scan (p < 0.001). The best predictor was combination of trabeculation and/or VUR (p < 0.001) (Figure). Among patients who maintained a non-trabeculated bladder without VUR during follow-up, 0/51 developed DMSA abnormalities compared with 31/79 who developed one or both (p < 0.001). Patients with trabeculations and/or VUR were more likely to start early CIC (8/51 vs. 44/79; p < 0.001) and have febrile UTI (11/51 vs. 50/79; p < 0.001). In those with trabeculations, CIC was associated with decreased incidence of febrile UTI (incidence rate ratio (IRR) 0.5, 95% CI 0.3-0.9); in those without trabeculations, CIC was associated with increased incidence of febrile UTI (IRR 1.8, 95% CI 1.1-3.1). CONCLUSIONS: VUR, bladder trabeculations, EFP ≥40 cm H20, IV ≥50% of EBC, and DPIV >10 cm H2O were associated with subsequent DMSA abnormalities in young children with SD managed expectantly. Many of these parameters were associated with febrile UTI and early CIC. The combination of trabeculations and/or VUR outperformed other UD parameters in identifying those high and low-risk for adverse urologic outcomes. Routine DMSA scan may have limited utility in patients with a non-trabeculated bladder without VUR, as none developed an abnormal DMSA. Most (71%) abnormal DMSAs were in patients with trabeculations and/or VUR following a febrile UTI. Given these findings and that incidence of febrile UTI may be lower in those with trabeculations while on CIC, patients with trabeculations and/or VUR should be managed aggressively to protect kidneys.

Expectant use of CIC in newborns with spinal dysraphism: Report of clinical outcomes.

PURPOSE: Report urologic outcomes among newborns with spinal dysraphism managed within an expectant clean intermittent catheterization (CIC) program. METHODS: Newborns were followed clinically and with serial ultrasound (US). Urodynamics (UD) and dimercaptosuccinic acid (DMSA) renal scan were obtained at 3-6 months, 1 year, 3 years, then as needed. Patients with initial evaluation after 6 months were excluded. RESULTS: Median follow-up was 3.2 years. 11/102 began catheterization for continence (median 4.0 years) and 47/102 did not start CIC. Of these, 2/58 developed a DMSA abnormality. 44/102 began CIC early, often for elevated storage pressures and febrile urinary tract infection (UTI). Of these, 20/44 developed a DMSA abnormality including 9 who had abnormality detected prior to starting CIC. Being on CIC or starting immediately upon recognition of new hydronephrosis, reflux, elevated filling pressures, or febrile UTI was associated with lower chance of DMSA abnormalities (4/17, 24%) compared to delaying CIC (16/27, 60%) (p= 0.03). CONCLUSIONS: CIC can be deferred until continence in select infants with a low risk of significant DMSA abnormality. However, immediate initiation of CIC upon recognition of risk factors is recommended as this was associated with fewer DMSA abnormalities than delaying CIC. Recommendations for expectantly-managed patients include close follow-up, serial US and UD, and prompt initiation of CIC upon recognition of new hydronephrosis, reflux, elevated storage pressures, or febrile UTIs.

Simple visual review of pre- to post-operative renal ultrasound images predicts pyeloplasty success equally as well as geometric measurements: A blinded comparison with a gold standard.

BACKGROUND: MAG3 diuretic renal scan remains the gold standard for determination of improvement in renal drainage following pyeloplasty for ureteropelvic junction obstruction. We hypothesized that (i) a change in geometric measurements between pre-operative and post-operative renal ultrasound (RUS) images and (ii) blinded simple visual review of images both would predict pyeloplasty success. OBJECTIVE: To determine if simple visual review and/or novel geometric measurement of renal ultrasounds can detect pyeloplasty failure. STUDY DESIGN: This study was a retrospective, blinded comparison with a gold standard. Included were children aged ≤18 years undergoing pyeloplasty at our institution from 2009 to 2015. For each kidney, representative pre-operative and post-operative RUS images were chosen. Our standard for pyeloplasty success was improved drainage curve on MAG3 and lack of additional surgery. Measurements for collecting system circularity, roundness, and renal parenchymal to collecting system area ratio (RPCSR) were obtained by three raters (Figure), who were blinded to the outcome of the pyeloplasty. Changes in geometric measurements were analyzed as a diagnostic test for MAG3-defined pyeloplasty success using ROC curve analysis. In addition, six reviewers blinded to pyeloplasty success reviewed pre-operative and post-operative images visually for improved hydronephrosis and categorized pyeloplasty as success or failure based on simple visual review of RUS. RESULTS: Fifty-three repaired renal units were identified (50 children). There were five pyeloplasty failures, four of which underwent revision or nephrectomy. While all geometric measurements could discriminate pyeloplasty failure and success, the geometric measurements that discriminated best between pyeloplasty failure and success were change in collecting system roundness and change in RPCSR. Consensus opinion among six blinded reviewers using simple visual review had a sensitivity of 94% and PPV of 100% with respect to identifying pyeloplasty success (AUC 0.97 (95% CI 0.93-1.0)). This was not significantly different from AUC for change in roundness (p = 0.09) or change in RPCSR (p = 0.1). DISCUSSION: Change in collecting system roundness and change in RPCSR were the most accurate geometric measurements in predicting pyeloplasty success. Simple visual review of ultrasound images for pyeloplasty success performed as well or better than geometric measurements. However, geometric measurements remain useful as a research tool or to communicate findings between clinicians. CONCLUSIONS: Complex geometric measurements of hydronephrosis or post-operative MAG3 scans are not needed if hydronephrosis is visually significantly improved, as simple visual review is highly sensitive for detecting pyeloplasty failure.

Pediatric surgical complications of major genitourinary reconstruction in the exstrophy-epispadias complex.

PURPOSE: Urinary continence is the goal of exstrophy-epispadias complex (EEC) reconstruction. Patients may require a continent urinary diversion (CUD) if they are a poor candidate for bladder neck reconstruction or are receiving an augmentation cystoplasty (AC) or neobladder (NB). This study was designed to identify the incidence of surgical complications among various bowel segments typically used for CUD. METHODS: A prospectively kept database of 1078 patients with EEC at a tertiary referral center from 1980 to 2012 was reviewed for major genitourinary reconstruction. Patient demographics, surgical indications, perioperative complications, and outcomes were recorded. RESULTS: Among reviewed EEC patients, 134 underwent CUD (81 male, 53 female). Concomitant AC was performed in 106 patients and NB in 11. Median follow up time after initial diversion was 5 years. The most common CUD bowel segments were appendix and ileum. The most common surgical complications after CUD were small bowel obstruction, post-operative ileus, and intraabdominal abscess. There was a significantly increased risk in the occurrence of pelvic or abdominal abscess when colon was used as a conduit compared to all other bowel segments (OR=16.7, 95% CI: 1.16-239) and following NB creation compared to AC (OR=39.4, 95% CI: 3.66-423). At postoperative follow-up, 98% of patients were continent of urine via their stoma. CONCLUSION: We report the largest series to date examining CUD in the EEC population. The increased risk of abdominal and pelvic abscesses in patients who receive a colon CUD and undergo NB compared to AC indicates that while surgical complications following major genitourinary reconstruction are rare, they do occur. Practitioners must be wary of potential complications that are best managed by a multi-disciplinary team approach.

Urologic complications of major genitourinary reconstruction in the exstrophy-epispadias complex.

OBJECTIVE: To present the authors' experiences with urologic complications associated with various techniques used to create a continent stoma (CS), augmentation cystoplasty (AC), and neobladder in the exstrophy-epispadias complex (EEC) population. METHODS: Retrospective review of medical records of patients who underwent CS with or without bladder augmentation were identified from an institutional review board-approved database of 1208 EEC patients. Surgical indications, tissue type, length of hospital stay, age, preoperative bladder capacity, prior genitourinary surgeries, postoperative urological complications, and continence status were reviewed. RESULTS: Among the EEC patients reviewed, 133 underwent CS (80 male, 53 female). Mean follow-up time after initial continent stoma was 5.31 years (range: 6 months to 20 years). Appendix and tapered ileum were the primary bowel segments used for the continent channel and stoma in the EEC population. The most common stomal complications in this population were stenosis, incontinence, and prolapse. Seventy-nine percent of EEC CS patients underwent AC primarily done with sigmoid colon or ileum. Eleven patients (8%) underwent neobladder creation with either colon or a combination of colon and ileum. Bladder calculi, vesicocutaneous fistula, and pyelonephritis were the most common non-stomal complications. Stomal ischemia was significantly increased in Monti ileovesicostomy compared to Mitrofanoff appendicovesicostomy in classic bladder exstrophy patients (p = 0.036). Furthermore, pyelonephritis was more than twice as likely in colonic neobladder than all other reservoir tissue types in the same cohort (OR = 2.53, 95% CI: 1.762-3.301, p < 0.001). CONCLUSIONS: To the best of the authors' knowledge, this is the largest study examining catheterizable stomas in the exstrophy population. While Mitrofanoff appendicovesicostomy is preferred to Monti ileovesicostomy because it is technically less challenging, it may also confer a lower rate of stomal ischemia. Furthermore, even though ileum or colon can be used in AC with equally low complication rates, practitioners must be wary of potential urologic complications that should be primarily managed by an experienced reconstructive surgeon.

Impact of nephrectomy on long-term renal function in non-syndromic children treated for unifocal Wilms tumor.

OBJECTIVE: The present study is designed to assess the long-term renal function of children who underwent radical nephrectomy for unifocal Wilms tumor. METHODS: A single institution retrospective cohort study of non-syndromic children treated with radical nephrectomy for unifocal Wilms tumor between 1995 and 2011 was performed to identify risk factors for decreased glomerular filtration rate (GFR). The primary endpoint was decrease in age-adjusted GFR below normal published ranges. The secondary endpoint was progression to chronic renal insufficiency (CRI). RESULTS: A total of 55 patients were identified in the cohort. Eight (15%) patients exhibited decreased age-adjusted GFR during the follow-up period, with 2 (4%) progressing to CRI. Increasing time between surgery and the last known GFR follow-up was associated with decreased GFR, with the normal GFR group having median follow-up of 7.32 years versus 11.47 years (p = 0.019) in the decreased GFR group. CONCLUSIONS: A trend toward decline in GFR was detected with longer follow-up. Longer follow-up may reveal that clinically significant decline in renal function occurs years following nephrectomy among a subset of Wilms tumor survivors, even among those who do not progress to end stage renal disease.