New frontiers on the molecular underpinnings of hypospadias according to severity.

Hypospadias, which is characterised by the displacement of the urethral meatus from its typical anatomical location in males, shows various degrees of severity. In this systematic review, we surveyed our current understanding of the genetics of isolated hypospadias in humans according to the severity of the condition. We found that sequencing and genotyping approaches were the preferred methods of study and that single nucleotide polymorphisms were the most common finding associated with hypospadias. Most genes fell into four gene-pathway categories related to androgens, oestrogens, growth factors, or transcription factors. Few hypospadias studies classify their findings by severity. Taken together, we argue that it is advantageous to take into consideration the severity of the condition in search of novel candidates in the aetiology of hypospadias. Abbreviations: AR: androgen receptor; ATF3: activating transcription factor 3; BMP4: bone morphogenetic protein 4; BMP7: bone morphogenetic protein 7; CYP17: steroid 17-alpha-hydroxylase/17,20 lyase; CYP1A1: cytochrome P450 1A1; CYP3A4: cytochrome P450 3A4; CNVs: copy number variants; DGKK: diacylglycerol kinase kappa; ESR1: oestrogen receptor 1; ESR2: oestrogen receptor 2; FGF8: fibroblast growth factor 8; FGF10: fibroblast growth factor 10; FGFR2: fibroblast growth factor receptor 2; HOXA4: homeobox protein Hox-A4; HOXB6: homeobox protein Hox-B6; HSD17B3: hydroxysteroid 17-beta dehydrogenase 3; MAMLD1: mastermind-like domain-containing protein 1; SF-1: splicing factor 1; SHH: sonic hedgehog; SNPs: single nucleotide polymorphisms; SOX9: SRY-box 9; SRD5A2: steroid 5 alpha-reductase 2; SRY: sex-determining region Y protein; STAR: steroidogenic acute regulatory protein; STARD3: StAR-related lipid transfer protein 3; STS: steryl-sulfatase; WT1: Wilms tumour protein; ZEB1: zinc finger oestrogen-box binding homeobox 1.

A Proteomics Signature of Mild Hypospadias: A Pilot Study.

Background and Objective: Mild hypospadias is a birth congenital condition characterized by the relocation of the male urethral meatus from its typical anatomical position near the tip of the glans penis, to a lower ventral position up to the brim of the glans corona, which can also be accompanied by foreskin ventral deficiency. For the most part, a limited number of cases have known etiology. We have followed a high-throughput proteomics approach to study the proteome in mild hypospadias patients. Methods: Foreskin samples from patients with mild hypospadias were collected during urethroplasty, while control samples were collected during elective circumcision (n = 5/group). A high-throughput, quantitative proteomics approach based on multiplexed peptide stable isotope labeling (SIL) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was used to ascertain protein abundance changes in hypospadias patients when compared to control samples. Results: A total of 4,815 proteins were quantitated (2,522 with at least two unique peptides). One hundred and thirty-three proteins from patients with mild hypospadias showed significant abundance changes with respect to control samples, where 38 proteins were increased, and 95 proteins were decreased. Unbiased functional biological analysis revealed that both mitochondrial energy production and apoptotic signaling pathways were enriched in mild hypospadias. Conclusions: This first comprehensive proteomics characterization of mild hypospadias shows molecular changes associated with essential cellular processes related to energy production and apoptosis. Further evaluation of the proteome may expand the search of novel candidates in the etiology of mild hypospadias and could also lead to the identification of biomarkers for this congenital urogenital condition.

Laparoscopic Single-Site Surgery in Pediatric Urology: Where Do We Stand Today?

Since the first description of the laparoendoscopic single-site surgery (LESS) in the pediatric urology population, various authors have shared their experiences and results. We aim to provide a review of current studies of LESS and share our experience with this modality. The current literature describes the use of LESS for most surgeries performed in the pediatric urology population with similar results to open and standard laparoscopic surgery. The authors have described their experiences with transabdominal and retroperitoneal nephrectomy, nephroureterectomy, pyeloplasty, orchidopexy, varicocelectomy, and renal cyst decortication. In our experience, LESS has taken a role for extirpative surgery since we use other modalities for upper tract reconstruction. The data available has validated LESS as safe and has demonstrated similar results to standard laparoscopic surgery and open surgery with better cosmetic results.

Salvage extravesical ureteral reimplantation after failed endoscopic surgery for vesicoureteral reflux.

PURPOSE: Open intravesical ureteral reimplantation has been reported to be uncomplicated following dextranomer/hyaluronic acid implantation. However, there are no known reports regarding extravesical ureteral reimplantation following dextranomer/hyaluronic acid failure. We reviewed our experience with extravesical ureteral reimplantation after dextranomer/hyaluronic acid failure. MATERIALS AND METHODS: We reviewed the charts of 30 patients who underwent extravesical ureteral reimplantation after dextranomer/hyaluronic acid failure. If reflux was initially bilateral and only a unilateral cure was achieved, the cured ureter was not reimplanted. Intraoperative complications, need for stenting or prolonged bladder catheterization, length of hospitalization and radiographic results were noted. RESULTS: At cystoscopy the dextranomer/hyaluronic acid implants were not seen in half of the patients. In the remaining 15 patients the blebs had moved caudally and/or were seen extravesically at the ureteral hiatus or along Waldeyer's sheath. Unilateral extravesical ureteral reimplantation was performed without difficulty in all patients and there were no intraoperative complications. Stents were left indwelling only in those patients who had undergone dismembered ureteral reimplantation. No patient required prolonged bladder drainage. All patients except 2 who had undergone additional procedures were discharged home within 24 hours postoperatively. There was no evidence of obstruction on postoperative renal sonography, and extravesical ureteral reimplantation was confirmed to be successful in all 24 patients with postoperative voiding cystourethrograms. CONCLUSIONS: Extravesical ureteral reimplantation can be performed without difficulty following dextranomer/hyaluronic acid implantation. Since extravesical ureteral reimplantation is less morbid and better tolerated than intravesical reimplantation, it is an excellent treatment option for patients with persistent unilateral vesicoureteral reflux following dextranomer/hyaluronic acid implantation. Furthermore, in cases in which vesicoureteral reflux is initially bilateral our data suggest that reimplantation of the successfully treated contralateral ureter can be avoided.

New contralateral vesicoureteral reflux following dextranomer/hyaluronic Acid implantation: incidence and identification of a high risk group.

PURPOSE: To our knowledge the incidence of NCVUR following the endoscopic treatment of VUR with Dx/HA has not been reported previously. We evaluated the outcomes in a group of patients to determine the incidence, and to attempt to identify risk factors. MATERIALS AND METHODS: A total of 126 children with primary unilateral VUR underwent unilateral Dx/HA implantation at our institutions. The incidence of NCVUR was determined by postoperative VCUG. Indications for surgery, patient age and gender, preoperative grade of VUR and volume of Dx/HA injected were assessed as possible risk factors for NCVUR. RESULTS: Of the patients 96 (76.2%) were female, and mean age was 4.8 years. The principal indications for Dx/HA implantation were persistent reflux in 56 patients (44.4%) and primary therapy in 51 (40.5%). At followup VCUG 17 patients (13.5%) had NCVUR. No variable independently appeared to influence the incidence of NCVUR. Statistical analysis suggests that females younger than 5 years have an increased incidence of NCVUR (13 of 62, or 21% vs 4 of 64, or 6.3% of the remaining patients, p = 0.016). CONCLUSIONS: NCVUR occurred in approximately 13% of our patients. Patients with higher preoperative VUR grade or a lower number of preoperative VCUGs and those undergoing treatment as primary therapy did not have an increased incidence. Girls younger than 5 years had the highest incidence of NCVUR, and initial bilateral injection may be a consideration for this group. Further effort directed at identifying the etiology and risk factors for NCVUR is needed.

Adolescent urology.

The area of adolescent urology encompasses a period of development that coincides with puberty. Disorders seen during this time either carry over from childhood (eg, hydronephrosis, enuresis, voiding dysfunction) or are early manifestations of urologic problems seen more commonly in adulthood (eg, urolithiasis, varicoceles). This article focuses on several areas of urology common to the adolescent.

Monoamniotic twin discordant for bilateral renal agenesis with normal pulmonary function.

A 22-year-old G4P3 woman with a twin pregnancy underwent an uncomplicated delivery at 35 weeks of gestation of normal-appearing twin boys. One of the boys returned 24 hours later with no voiding since birth. He was doing well with no respiratory difficulties and normal physical examination findings. Renal/bladder ultrasonography and computed tomography of the abdomen and pelvis revealed no evidence of kidneys. The admission laboratory values were consistent with renal failure. A peritoneal dialysis catheter was inserted and peritoneal dialysis started. Our patient died at 2 months old secondary to complications from the peritoneal dialysis. We describe the unusual case of a monoamniotic twin discordant for bilateral renal agenesis with normal pulmonary function. This case shows the importance of normal renal function in the production of amniotic fluid and its relationship to the proper development of the pulmonary system.

Renal transit time with MR urography in children.

PURPOSE: To prospectively evaluate use of dynamic contrast material-enhanced magnetic resonance (MR) urography for measurement of renal transit time (RTT) of a contrast agent through the kidney and collecting system so as to identify obstructive uropathy in children. MATERIALS AND METHODS: One hundred twenty-six children suspected of having hydronephrosis were hydrated prior to undergoing both conventional and dynamic contrast-enhanced MR urography of the kidneys and urinary tract. A three-dimensional sequence was used to track passage of contrast agent through the kidneys. Time between the appearance of contrast material in the kidney and its appearance in the ureter at or below the level of the lower pole of the kidney was defined as RTT. Bland-Altman plots were used to quantify intra- and interobserver performance. In 30 children, a nuclear medicine renogram was also obtained, and the half-life of renal signal decay after furosemide administration was derived and compared with the MR imaging RTT by using receiver operating characteristic curves. RESULTS: On the basis of RTT, kidneys were classified as normal (RTT RTT 490 seconds). Inter- and intraobserver agreement indicated that the technique is both robust and reproducible. Receiver operating characteristic analysis for comparison of results of MR imaging and diuretic renal scintigraphy showed good agreement between the modalities, with a mean area under the curve of 0.90. CONCLUSION: When used in conjunction with morphologic images obtained in the same examination, RTT generally allowed normal kidneys to be differentiated from obstructed and partially obstructed kidneys.

A prospective study comparing ultrasound, nuclear scintigraphy and dynamic contrast enhanced magnetic resonance imaging in the evaluation of hydronephrosis.

PURPOSE: A combination of nuclear medicine, ultrasound and voiding cystourethrography is typically used to investigate hydronephrosis in children. A major problem is the lack of an accepted gold standard to assess obstruction. In some cases the anatomy is unclear. By combining anatomical and functional information in one study, magnetic resonance imaging (MRI) has the potential of providing superior information regarding hydronephrosis. We evaluate the role of dynamic enhanced MRI and compare it to other imaging modalities in the investigation of pediatric hydronephrosis. MATERIALS AND METHODS: One hundred dynamic contrast enhanced MRIs were performed in 96 children (35 girls and 61 boys, mean age 4 years [range 1 month to 17 years]). The information from the various imaging modalities was compared. RESULTS: The MRI protocol was acceptable to all families and was performed without complications in all patients. The morphological imaging with MRI was superior to conventional imaging in all cases. The split renal function as calculated by nuclear and MRI scans was compared in 71 cases, and the correlation coefficient was r2 = 0.93. The combination of ultrasound and a nuclear medicine study correlated with the final diagnosis of the MRI in 50 of 64 studies (78%). Of the 14 studies that differed 8 were obstructed on MRI but not on the nuclear studies, and 5 were not obstructed on MRI but were obstructed on the nuclear studies. One patient believed to have ureteropelvic junction obstruction on nuclear medicine scan had ureterovesical junction obstruction on MRI. The final diagnoses by MRI were ureteropelvic junction obstruction in 26 children, primary ureterovesical junction obstruction in 14, dilated but not obstructed systems in 35, duplex systems in 13, multicystic dysplastic kidneys in 5, unilateral small scarred kidney in 1, acute pyelonephritis in 2, renal mass in 1, bilateral polycystic kidneys in 1 and normal study in 9. Sedation was administered safely without any complications. CONCLUSIONS: Dynamic contrast enhanced MRI provides equivalent information about renal function but superior information regarding morphology in a single study without ionizing radiation. MRI has the potential to replace the currently used combination of other imaging modalities in the investigation of hydronephrosis in children.

Minimally invasive treatment of vesicoureteral reflux with endoscopic injection of dextranomer/hyaluronic acid copolymer: the Children's Hospitals of Atlanta experience.

PURPOSE: Emerging data demonstrate that injection of dextranomer/hyaluronic acid (Dx/HA) copolymer (Deflux, Q-Med Scandinavia, Uppsala, Sweden) is a safe and effective treatment for most patients with vesicoureteral reflux (VUR). We sought to determine the efficacy and factors predictive of outcome in patients treated with Dx/HA. MATERIALS AND METHODS: A total of 180 children 7 months to 15 years old (mean age 4.6 years) underwent subureteral injection of Dx/HA for VUR between October 2001 and February 2003. Dx/HA was injected submucosally within or beneath the intramural ureter. The average volume of injected material was measured for each ureter. At 2 weeks and 3 months postoperatively bladder ultrasounds were performed to measure the volume of Dx/HA (mm3) in the trigone using the volume of an ellipsoid (V = 4/3pir(1)r(2)r(3)). Renal sonography was performed to determine whether hydronephrosis was present. At 3 months fluoroscopic voiding cystourethrograms were used to evaluate for the presence of VUR. RESULTS: A total of 292 ureters in 180 children were treated (112 bilateral cases). There were 141 girls and 39 boys. Mean maximum grade per patient was 2.6 (out of 5). Average injected volume per ureter was 0.83 +/- 0.03 ml (830 +/- 30 mm3). At 2 weeks the average measured volume was 663 +/- 70 mm3 (18% decrease from original volume), which decreased an additional 1% by 3 months to 656 +/- 103 mm3. There were no cases of hydronephrosis at up to 12 months postoperatively.There were 134 patients with at least 3 months of followup. After 1 treatment 72% (96) were cured (grade 0), while 55% of the failures (21 of 38) were improved. New contralateral VUR was seen in 6 patients (4.5%) who had neither a history of VUR nor an abnormal appearing ureteral orifice at cystoscopy. A lower success rate (60%) was seen in the first 20 patients compared with the last 20 patients (80%). The cure rate per grade was 90% for grade I, 82% for grade II, 73% for grade III and 65% for grade IV reflux. Local migration of material caudal to the ureteral orifice was seen in 61% of patients (11 of 18) at the time of reinjection of Dx/HA after initial treatment failure. There was no statistically significant difference in age, grade, volume injected, bilaterality or gender when successes were compared with failures. CONCLUSIONS: The majority of patients (72%) undergoing minimally invasive treatment of VUR with Dx/HA are cured after 1 treatment. Contralateral treatment of nonrefluxing ureters should be considered in view of the increased incidence of new reflux (4.5%) and absence of morbidity with Dx/HA injection. There is a definite learning curve with injection therapy. The location of injected material and experience with the technique appear to correlate with the outcome of the procedure.

Complete bladder, urethral, and vaginal duplication in a 50-year-old woman.

We present a rare case of a 50-year-old woman with complete bladder, urethral, and vaginal duplication without previous urogenital system reconstruction. Our patient demonstrated a rare embryologic defect with complete bladder, urethral, and vaginal duplication without any functional dysfunction. She was able to reach adulthood without reconstructive surgery. This case allowed the unique opportunity of evaluating these urogenital anomalies at a later point in life.

Blunt traumatic hematuria in children. Is a simplified algorithm justified?

PURPOSE: We determined whether radiographic evaluation is indicated in all children with traumatic hematuria. MATERIALS AND METHODS: We retrospectively reviewed the records of 110 children from 1992 to 1999 diagnosed with blunt trauma and hematuria. It is routine practice at our emergency department to perform radiographic evaluation in all children with hematuria regardless of the degree. Each chart was evaluated for the mechanism of injury, degree of hematuria, hypotension, imaging studies, renal injury, renal anomalies, associated injuries and outcome. RESULTS: A total of 110 patients 1 to 18 years old (mean age 9) were identified. The most common mechanism of injury was motor vehicle accident in 37 children (34%), followed by a fall in 32 (29%). Grades I to V renal injury was present in 5, 6, 6, 6 and 1 cases, respectively (22%), while 1 (0.9%) involved ureteropelvic junction avulsion. No child had renal pedicle injury. In 9 patients renal anomalies were detected incidentally. Of the 110 patients 101 underwent radiographic evaluation, including computerized tomography in 97 (88%). The 24 patients (22%) with significant renal injury and all with incidentally diagnosed renal anomalies had 50 or greater red blood cells per high power field on urinalysis, while 1 with ureteropelvic junction avulsion presented without hematuria. Hypotension was present in only 3 patients (2.7%), who also had associated injuries, including 2 who presented with renal injury. All 3 with associated injuries. Associated injuries were identified in 11 of 25 patients (44%). The 9 patients (8%) who did not undergo radiographic imaging had negative results on repeat urinalysis with an excellent outcome. CONCLUSIONS: We recommend that radiological evaluation consisting of abdominal and pelvic computerized tomography should be performed only in patients with 50 or greater red blood cells on urinalysis, hypotension at presentation to the emergency room or based on the severity of mechanism of injury, for example high speed motor vehicle accident deceleration injuries. The patient who presented with ureteropelvic junction avulsion without hematuria would have undergone imaging considering the mechanism of injury and number of associated injuries.

Metabolic risk factors for stone formation in patients with cystic fibrosis.

PURPOSE: Cystic fibrosis is characterized by chronic pulmonary disease, insufficient pancreatic and digestive function, and abnormal sweat concentrations. Patients with cystic fibrosis also have an increased incidence of nephrolithiasis. We compared the results of metabolic evaluation in patients with cystic fibrosis with and without nephrolithiasis. MATERIALS AND METHODS: A total of 496 patients were evaluated at our center, including 98 with a mean age of 25 years who had cystic fibrosis and complete metabolic evaluation available between 1996 and 2000. Of these patients 13 (13%) had a history of nephrolithiasis. The records were reviewed for clinical characteristics and all patients underwent metabolic evaluation, including serum electrolyte measurement and 24-hour urine collection. Statistical analysis was done to compare the stone versus nonstone groups. RESULTS: The incidence of nephrolithiasis in our study was 3%. We identified 13 patients 16 to 41 years old (mean age 27) with nephrolithiasis, of whom 62% had had multiple episodes. Flank pain was the presenting symptom in 9 of the 13 cases (69%). Renal ultrasound and computerized tomography were the most common imaging modalities. In 9 cases stones were passed without intervention, extracorporeal shock wave lithotripsy was required in 2 and ureteroscopy with stone extraction was done in 2. Calcium oxalate was the dominant stone composition in the 9 patients in whom stone analysis was performed. Metabolic evaluation of the stone versus no stone groups showed elevated urinary oxalate (45.5 versus 42.5 mg./24 hours), relative calcium oxalate supersaturation (5.3 versus 7.2) and decreased urinary citrate in the 2 groups. There was a statistical difference in citrate excretion with lower levels in stone formers (102 versus 218 mg./24 hours, p = 0.0007). CONCLUSIONS: Patients with cystic fibrosis have an increased incidence of nephrolithiasis and are at high risk for recurrence. Metabolic evaluation is indicated in all patients with cystic fibrosis and urolithiasis since most have hyperoxaluria, urinary calcium oxalate supersaturation and decreased urinary citrate. Correcting detected stone risk factors in these cases may decrease stone recurrence.