ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development.

Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10-08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10-19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development

Bladder dysfunction in boys with posterior urethral valves

Posterior urethral valve (PUV) is a congenital urethhhhal urethral obstruction only affecting boys. As a result of the obstruction in fetal life, these boys often have a persisting bladder dysfunction, which is one of the main causes of the late onset renal failure seen in 1/3 of the boys and is also responsible for the delayed achievement of continence. The aim of this study was to characterize the bladder dysfunction from infancy through childhood and adolescence in boys with neonatally diagnosed PUV with the intention of designing a bladder treatment regimen starting in infancy. Paper I: 16 infant boys with PUV were followed with repeated standard cystometries. At presentation the bladders were hypercontractile with low capacity. During the first three years of life the urodynamic pattern changed, with vanishing hypercontractility and increasing bladder capacity, even though the instability remained unchanged. Paper II: 12 boys were followed with standard cystometries between 4 and 12 years of age and compared with a group of 6 postpubertal boys with PUV. The urodynamic pattern continued to change, with decreasing instability and contractility. A major problem was emptying difficulties.Paper III: The voiding pattern during the day versus the night in 10 incontinent and 6 continent boys with PUV was evaluated by long-term natural filling cystometry. The voiding pattern, with small frequent voidings during the day and few or no voidings during the night with high bladder volumes in the morning, could be explained by pronounced instability during the day whereas the bladders were stable during the night. Paper IV: The method of "4 hour voiding observation" was presented as a non-invasive method for basic assessment of bladder function in non-toilet trained children and the voiding pattern in 43 healthy infants was demonstrated.Paper V: The voiding pattern, with special attention to emptying difficulties, in 25 small children with PUV compared to healthy children of corresponding age, was evaluated with the "4 hour voiding observation".Conclusions: Boys with PUV have a bladder dysfunction with a changing urodynamic pattern over time with decreasing contractility and instability. In small boys the instability was pronounced during daytime while during the night the bladders were mainly stable. Most boys with PUV and bladder dysfunction end up with a decompensated bladder. A major problem was bladder emptying difficulties. The "4 hour voiding observation" is an excellent non-invasive method of identifying those patients in need of early bladder treatment, i.e. with clean intermittent catheterisation

The Swedish Reflux Trial in Children: V. Bladder Dysfunction.

PURPOSE: We investigated the prevalence and types of lower urinary tract dysfunction in children with vesicoureteral reflux grades III and IV, and related improved dilating reflux, renal damage and recurrent urinary tract infection to dysfunction. MATERIALS AND METHODS: A total of 203 children between ages 1 to less than 2 years with reflux grades III and IV were recruited into this open, randomized, controlled, multicenter study. Voiding cystourethrography and dimercapto-succinic acid scintigraphy were done at study entry and 2-year followup. Lower urinary tract function was investigated by noninvasive methods, at study entry with 4-hour voiding observation in 148 patients and at 2 years by structured questionnaire and post-void residual flow measurement in 161. RESULTS: At study entry 20% of patients had lower urinary tract dysfunction, characterized by high bladder capacity and increased post-void residual urine. At 2 years there was dysfunction in 34% of patients. Subdivision into groups characteristic of children after toilet training revealed that 9% had isolated overactive bladder and 24% had voiding phase dysfunction. There was a negative correlation between dysfunction at 2 years and improved dilating reflux (p = 0.002). Renal damage at study entry and followup was associated with lower urinary tract dysfunction at 2 years (p = 0.001). Recurrent urinary tract infections were seen in 33% of children with and in 20% without dysfunction (p = 0.084). CONCLUSIONS: After toilet training a third of these children with dilating reflux had lower urinary tract dysfunction, mainly voiding phase problems. Dysfunction was associated with persistent reflux and renal damage while dysfunction at study entry did not predict the 2-year outcome

Copy number variants suggest different molecular pathways for the pathogenesis of bladder exstrophy

Bladder exstrophy is a rare congenital malformation leaving the urinary bladder open in the midline of the abdomen at birth. There is a clear genetic background with chromosome aberrations, but so far, no consistent findings apart from 22q11-duplications detected in about 2%–3% of all patients. Some genes are implicated like the LZTR1, ISL1, CELSR3, and the WNT3 genes, but most are not explained molecularly. We have performed chromosomal microarray analysis on a cohort of 140 persons born with bladder exstrophy to look for submicroscopic chromosomal deletions and duplications. Pathogenic or possibly pathogenic microdeletions or duplications were found in 16 patients (11.4%) and further 9 with unknown significance. Two findings were in regions linked to known syndromes, two findings involved the same gene (MCC), and all other findings were unique. A closer analysis suggests a few gene networks that are involved in the pathogenesis of bladder exstrophy; the WNT-signaling pathway, the chromosome 22q11 region, the RIT2 and POU families, and involvement of the Golgi apparatus. Bladder exstrophy is a rare malformation and is reported to be associated with several chromosome aberrations. Our data suggest involvement of some specific molecular pathways

Evaluation of the ISL1 gene in the pathogenesis of bladder exstrophy in a Swedish cohort

Bladder exstrophy is a congenital closure defect of the urinary bladder with a profound effect on morbidity. Although the malformation is usually sporadic, a genetic background is supported by an increased recurrence risk in relatives, higher concordance rates in monozygotic twins and several associated chromosomal aberrations. Recently, the ISL1 gene was presented as a candidate gene for bladder exstrophy and epispadias complex (BEEC) development in two different studies. In our study, we screened for genetic variants in the ISL1 gene in DNA from 125 Swedish patients using Sanger sequencing and array-CGH analysis. In addition, we evaluated ISL1 expression in RNA of human bladder during embryonic and fetal weeks 5–10 relative to that in lung tissue (week 9). In total, 21 single-nucleotide variants were identified, including a potentially novel missense variant, c.137C>G p.(Ala46Gly), substituting a conserved amino acid. This variant was inherited from an unaffected mother. No structural variants were identified. RNA sequencing revealed ISL1 mRNA expression during the critical time frame of human bladder development. In conclusion, we did not detect any known or likely pathogenic variants in the ISL1 gene in 125 Swedish BEEC patients, indicating that variation in the ISL1 gene is not a common genetic mechanism of BEEC development in the Swedish population

Bowel control, bladder function, and quality of life in children with cloacal malformations

Introduction: Long-term outcomes of cloacal malformations remain unclear. We evaluated postoperative bowel control, bladder function and quality of life in patients under 18 years of age with cloaca. Materials and methods: This was a multi-center cross-sectional observational study accomplished by the Nordic Pediatric Surgery Research Consortium. Patients with a cloacal malformation, 4–17 years of age, were eligible. Data including patient characteristics, surgical procedures, and complications were retrieved from case records. Established questionnaires with normative control values evaluating bowel function, bladder function, and health-related quality of life (HRQoL) were sent to the patients and their caregivers. The study was approved by the participating center's Ethics Review Authorities. Results: Twenty-six (67%) of 39 eligible patients with median age 9.5 (range, 4–17) years responded. Twenty-one (81%) patients had a common channel ≤3 cm. Imaging confirmed sacral anomalies in 11 patients and spinal cord abnormalities in nine. Excluding patients with stoma (n = 5), median bowel function score was 12 [7-19], and 5 patients (20%) reported a bowel function score ≥17, approaching normal bowel control level. Bowel management increased proportion of socially continent school-aged children to 52%. Six (23%) patients had a permanent urinary diversion or used clean intermittent catheterization (CIC), while majority (70%) of the remaining patients were urinary continent. The reported HRQoL was comparable to healthy Swedish children. Conclusion: Whilst well-preserved spontaneous bowel control was rare, a majority of patients were dry for urine without any additional procedures. Few patients experienced social problems or negative impact on HRQoL due to bladder or bowel dysfunction. Level of evidence: Level IV

Lifelong Congenital Urology: The Challenges for Patients and Surgeons

Context: Patients born with complex congenital genitourinary anomalies (including bladder exstrophy, cloacal exstrophy, epispadias, neurogenic bladder, hypospadias and posterior urethral valves) often require major reconstructive surgery in childhood. These conditions, their treatment and sequelae require lifelong follow-up. This has created the need for adult urologists to provide care as these patients grow into adults. Objective: To evaluate current strategies for transition and provide a current position statement with examples of the challenges faced by patients and their health care teams as a result of these conditions and their treatment. Evidence acquisition: Each of the authors was asked to provide a 500-word synthesis, based on current literature; to highlight the challenges faced in an area of their expertise. Evidence synthesis: The authors assembled in March 2018 to form a consensus based on the data gathered. The aforementioned sections were reviewed and following the consensus discussion the paper was formulated and reviewed. Conclusions: Lifelong care of congenital problems is challenging and essential for many but not all. Expertise is needed to provide the best care for patients and make the best use of resources. Specialist centres appear to be the most effective and safe model. In the long term it would be ideal to establish an evidence base focused on the common long-term problems with these conditions to ensure excellent care with appropriate expertise. Patient summary: Patients born with complex congenital anomalies of the genitourinary system require specialist care in childhood. Many will need lifelong care to manage their condition and the treatment of it. There is growing interest in this area of medicine and this consensus statement addresses the need for lifelong care in this group. The aim is to ensure that all patients that need care at any age are able to find what they need. (C) 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved