Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD).

Disorders of sex development (DSDs) are a diverse group of conditions where the chromosomal, gonadal or anatomical sex can be atypical. The highly heterogeneous nature of this group of conditions often makes determining a genetic diagnosis challenging. Prior to next generation sequencing (NGS) technologies, genetic diagnostic tests were only available for a few of the many DSD-associated genes, which consequently had to be tested sequentially. Genetic testing is key in establishing the diagnosis, allowing for personalised management of these patients. Pinpointing the molecular cause of a patient's DSD can significantly impact patient management by informing future development needs, altering management strategies and identifying correct inheritance pattern when counselling family members. We have developed a 30-gene NGS panel, designed to be used as a frontline test for all suspected cases of DSD (both 46,XX and 46,XY cases). We have confirmed a diagnosis in 25 of the 80 patients tested to date. Confirmed diagnoses were linked to mutations in AMH, AMHR2, AR, HSD17B3, HSD3B2, MAMLD1, NR5A1, SRD5A2 and WT1 which have resulted in changes to patient management. The minimum diagnostic yield for patients with 46,XY DSD is 25/73. In 34/80 patients, only benign or likely benign variants were identified, and in 21/80 patients only variants of uncertain significance (VOUS) were identified, resulting in a diagnosis not being confirmed in these individuals. Our data support previous studies that an NGS panel approach is a clinically useful and cost-effective frontline test for patients with DSDs.

Tubulocystic anomalies of the mesonephric duct associated with ipsilateral renal dysgenesis.

INTRODUCTION: Renal agenesis and multicystic dysplastic kidney (MCDK) are usually associated with either an absent or atretic ureter. Occasionally, these renal anomalies may be associated with a dilated tortuous ureter, ureterocele or other cystic malformation of mesonephric duct (MND) remnants. OBJECTIVES: The objective of this study was to identify and classify anatomical variants of tubulocystic remnants of the MND, with a secondary focus on natural history and management outcomes. PATIENTS AND METHODS: A retrospective cohort study of patients seen in the study institution between 2007 and 2014 with a tubulocystic abnormality of MND structures associated with either MCDK or renal agenesis was conducted. Medical imaging and progress notes were reviewed for all patients. Data collected included anatomical information, surgical intervention, histology and outcomes of both conservatively managed and surgically resected MND remnant structures. RESULTS: Nineteen patients were identified, 5 girls and 14 boys. Median age at presentation was 4.6 years. Anomalies of the MND occurred on the left in 9 patients and on the right in 10 patients. Mean follow-up was 3.4 years. Patients fell into 3 distinct anatomical groups: Type I, including orthotopic remnants corresponding to ureteric bud structures (ureter and trigone); Type II, including ectopic MND remnants of ureteric bud structures, and Type III, including complex remnants corresponding to MND structures other than those from ureteric bud (vas, epididymis and seminal vesicles). Anomalies of structures arising from urogenital sinus and paramesonephric ducts were also identified. Most patients were asymptomatic and successfully managed conservatively. Transvesical puncture of trigonal cysts provided effective decompression in 5 patients. Partial or complete MCDK regression was seen in 7 patients, whereas MND cystic anomalies did not regress spontaneously. DISCUSSION: When MND tubulocystic structures persist along with renal agenesis or MCDK, most arise from ureteric bud structures in an orthotopic position as a ureterocele with or without a blind-ending ureter-like structure. Less commonly, ureteric bud structures insert ectopically into the urogenital tract, or tubulocystic structures arising from the remainder of the MND occur. Embryogenesis of other urogenital structures may also be abnormal, and conditions such as Zinner syndrome and obstructed hemivagina and ipsilateral renal agenesis syndrome should be considered. CONCLUSIONS: Complications are uncommon, and surgical intervention should be limited to symptomatic patients. Remnants of metanephric blastema may involute, but MND remnants persist.

Nadir creatinine in posterior urethral valves: How high is low enough?

INTRODUCTION: Large retrospective studies of people with posterior urethral valves (PUV) have reported chronic renal insufficiency (CRI) in up to one third of the participants and end-stage renal failure in up to one quarter of them. Nadir creatinine (lowest creatinine during the first year following diagnosis) is the recognised prognostic indicator for renal outcome in PUV, the most commonly used cut-off being 1 mg/dl (88.4 umol/l). OBJECTIVE: To conduct a statistical analysis of nadir creatinine in PUV patients in order to identify the optimal cut-off level as a prognostic indicator for CRI. STUDY DESIGN: Patients treated by endoscopic valve ablation at the present institution between 1993 and 2004 were reviewed. Chronic renal insufficiency was defined as CKD2 or higher. Statistical methods included receiver operating characteristic (ROC) curve analysis, Fisher exact test and diagnostic utility tests. Statistical significance was defined as P < 0.05. RESULTS AND DISCUSSION: Nadir creatinine was identified in 96 patients. The median follow-up was 9.4 (IQR 7.0, 13.4) years. A total of 29 (30.2%) patients developed CRI, with nine (9.4%) reaching end-stage renal failure. On ROC analysis, Nadir creatinine was highly prognostic for future CRI, with an Area Under the Curve of 0.887 (P < 0.001). Renal insufficiency occurred in all 10 (100%) patients with nadir creatinine >88.4 umol/l compared with 19 of 86 (22.2%) patients with lower nadir creatinine (P < 0.001). As a test for future CRI, a nadir creatinine cut-off of 88.4 umol/l gave a specificity of 100%, but poor sensitivity of 34.5%. Lowering the cut-off to 75 umol/l resulted in improvement in all diagnostic utility tests (Table). All 14 (100%) patients with nadir creatinine >75 umol/l developed CRI, compared with 15 of 82 (18.3%) patients with lower nadir creatinine (P < 0.001). Sensitivity only approached 95% at 35 umol/l, at which level specificity was low (Table). Two out of 36 (5.6%) patients with nadir creatinine <35 umol/l developed CRI. Multivariate analysis found recurrent UTI (OR 4.733; CI 1.297-17.280) and nadir creatinine >75 umol/l (OR 48.988; CI 4.9-490.11) to be independent risk factors for progression to CRI. Using cut-off values of 35 umol/l and 75 umol/l, patients can be stratified into low-, intermediate- and high-risk groups, with development of CRI in 5.3%, 28.3% and 100%, respectively (P <0.001). The stage of CKD was higher in higher risk groups. CONCLUSION: Patients with nadir creatinine >75 umol/l (0.85 mg/dl) should be considered at high risk for CRI, while patients with nadir creatinine ≤35 umol/l (0.4 mg/dl) should be considered low risk. Patients with nadir creatinine between these two values have an intermediate risk of CRI.

Neuronavigation with the universal probe to access intracranial targets.

INTRODUCTION: The universal probe is a tool devised to allow navigation-directed biopsies and drainage procedures to be performed in a simple manner using a single hardware and software. AIM: To assess the efficacy and safety of the universal probe. RESULTS: We used the universal probe in a total of 17 patients for 10 biopsies and 8 drainage procedures. We were able to achieve our set objectives in all 18 procedures. We did not encounter any complications using this device. CONCLUSION: The universal probe enabled a variety of navigation-based procedures to be carried out using only a single software and hardware.

Gamma knife stereotactic radiosurgery for thalamic & brainstem cavernous angiomas.

OBJECTIVE: To determine the safety and efficacy of Gamma Knife stereotactic radiosurgery (GKS) in the treatment of patients with symptomatic cavernous angiomas (CA) of the brainstem or thalamus, by comparing overall outcome to the natural history of the disease. METHODS: Over 10 years a series of 16 consecutively presenting patients (M = 9, F = 7) with thalamic or brainstem CA were treated with GKS to a single lesion, specifically excluding the haemosiderin ring from the target. Within the year prior to treatment eight patients had suffered one symptomatic haemorrhage and eight had suffered more than one symptomatic haemorrhage. Mean age at treatment was 38.9 (15-55) years. Mean prescription dose 13.31 Gray (11.0 Gy-16.0 Gy). Patients were followed up radiologically and, more importantly, clinically for a mean period of 43.8 (11-101) months, median 36 months. RESULTS: One patient suffered recurrent haemorrhage at 23 months post-GKS, but has not re-bled in the following 61 months. One patient died of thalamic haemorrhage from the treated lesion at 90 months. One patient was lost to follow up. There have been no other clinical episodes or radiological findings to suggest post-GKS haemorrhage in the remaining 13 patients, and no other complications were observed in the treated population. The annual haemorrhage rate within the first two years post GKS was 3.72% and the annual haemorrhage rate 2 years post GKS was 3.59% per annum. CONCLUSION: With the dose regimens described, GKS is safe and effective in the treatment of thalamic and brainstem CA, as assessed by significant reduction in observed rate of re-haemorrhage over that expected from the known natural history of those CAs which have already demonstrated a tendency to haemorrhage in highly eloquent areas.

An association between cerebral aneurysm re-bleed and CT angiography--more than a coincidence?

Rupture of cerebral aneurysm during CT angiogram is a rare occurrence. Here we present such a case where an aneurysmal re-rupture during CT angiogram was demonstrated.

Health-related quality of life in patients reliant upon mitrofanoff catheterisation.

OBJECTIVE: Aim of the study was determine health care outcomes from the patients' perspective in patients reliant on Mitrofanoff catheterisation for bladder emptying. SUBJECTS/PATIENTS: Patients over the age of 16 dependent on Mitrofanoff catheterisation for bladder emptying were asked to complete a health care outcome questionnaire, the SF-36 (®) Health Survey v2. Quality of life measures for 8 health concepts were compared against published data for the normal population. RESULTS: Out of a total of 25 patients who were eligible for enrolment into our study, we were able to contact 19 patients. The norm-based score for Physical Functioning (PF=50.4), Role Physical (RP=53.8), Bodily Pain (BP=55.6), Vitality (VT=56.9), Social Functioning (SF=51.5), Role Emotional (RE=52.2), and Mental Health (MH=54.6) were all higher than those reported within the normal population (normal=50.0). Physical and mental component summary measures were higher than in the normal population. When compared against age-matched norms our patient group scored higher than the normal population for all measures except Physical Functioning (50.4 vs. 53.4) and physical component summary (51.9 vs. 53.5). The self-reported scores for Vitality, Mental Health and the mental component summary were all statistically significantly better than those seen in the age-matched control population (p<0.01). CONCLUSIONS: Quality of life in patients dependent on Mitrofanoff catheterisation for bladder emptying is good. The SF-36 measures 8 major health care outcomes and in our patients these measures of health were similar to those seen in the general population, rather than the poorer outcomes reported in patients with other chronic medical conditions.

A haemostatic agent delivery system for endoscopic neurosurgical procedures.

In endoscopic neurosurgery problems with haemostasis due to poor access exist. We have developed a system which allows the delivery of a variety of haemostatic agents in a more efficacious manner. The system has been used successfully in endoscopic skull base surgery and endoscopic surgery within the parenchyma of the brain using tube systems.

Laparoscopic vascular relocation: alternative treatment for renovascular hydronephrosis in children.

AIMS: The standard treatment for pelviureteric junction obstruction (PUJO) has been dismembered pyeloplasty. The open surgical, Hellström procedure in which crossing polar vessels are relocated, has been an option in adult urological practice. We present our experience with laparoscopic vascular relocation in children. METHODS: Data were retrospectively gathered on all patients who underwent laparoscopic relocation of lower pole vessels (LRLPV) at our institution between July 2004 and March 2008. Follow-up ultrasounds and MAG3 were obtained. RESULTS: LRLPV was performed in 10 boys and 9 girls. Patients were between 5.8 and 15.25 years (median 9.9 years). They presented with recurrent abdominal pain (n = 17), urinary tract infections (n = 7) and haematuria (n = 3). On ultrasound, MAG3 and retrograde studies they had hydronephrosis, obstructed drainage and a normal calibre ureter with a sharp cut-off. They were further assessed at laparoscopy and were found to have aberrant lower pole crossing vessels. All underwent laparoscopic mobilization of the lower pole vessels from the region of the PUJ thereby freeing the junction and relocating them superiorly onto the anterior wall of the pelvis. The median operating time was 120 min (range 60-240 min). The median hospital stay was 2 days (range 1-3 days). They were followed up for a median period of 12 months (range 6-36 months). All patients have remained asymptomatic. Ultrasound done at 6 months showed decreased hydronephrosis. MAG3 study showed improved drainage in 17, while 1 had poor drainage. This patient remains symptom free and is under regular follow up. CONCLUSION: Laparoscopic vascular relocation is an unconventional technique in carefully selected patients with PUJO. It obviates disrupting an intrinsically normal PU junction and treats the cause rather than the effect. Our intermediate-term results are encouraging and further long-term assessment is needed.

Urinomas protect renal function in posterior urethral valves--a population based study.

BACKGROUND/PURPOSE: Urinomas have been thought to protect renal function in boys with posterior urethral valves (PUVs), although recent reports have disputed this. This study tested the hypothesis that urinomas protect global renal function in boys with PUV. METHODS: A retrospective analysis of all boys with PUV presenting to a tertiary unit derived from a region with an estimated population of 5.5 million was performed. Comparisons of the initial nadir creatinine, current creatinine, and renal status score (RSS) were made between those with and without urinomas. The RSS was derived from nephrology assessment of current renal status (0 = normal to 4 = end-stage renal failure or transplantation). Results were given as median (range), except for RSS, which was given as mean +/- SEM. P < or = .05 was regarded as significant. RESULTS: During 1989-2009, 9 of 89 PUV boys were diagnosed with urinomas. Initial nadir creatinine was statistically lower in boys with urinomas (31 [18-44] vs 45 [20-574] mumol/L, P < .01). Length of follow-up was similar (5.1 [2.2-17.3] vs 5.9 [1.8-19.7] years, P = .59). Follow-up creatinine was significantly lower in urinoma boys (44 [25-77] vs 61 [29-1227] micromol/L, P < .05), as was the RSS (0.14 +/- 0.14 vs 0.91 +/- 0.14, P < .01). No urinoma boys progressed to end-stage renal failure or required transplant. CONCLUSION: This population-based study of PUV boys demonstrates that urinomas reduce nadir creatinine and significantly protect long-term global renal function.

Silent But Giant: Giant ureteric calculus in a 7-year-old boy.

Giant ureteric calculi are extremely rare in children. We present a case of a child who was originally admitted for observation following non-accidental injury and had an episode of painless haematuria as an inpatient. Ultrasonography demonstrated left hydronephrosis and a 2cm echogenic area in the proximal ureter. A plain abdominal radiograph surprisingly revealed two left ureteric calculi, one 7cm and the other 4cm in length. Stone extraction was achieved using an open left ureterolithotomy and pyelolithotomy.

Retroperitoneal approach for laparoscopic nephrectomy is feasible in a child with difficult access due to severe scoliosis.

Retroperitoneal minimal access surgery has been widely described and practiced in many paediatric urology units. However, retroperitoneal laparoscopic nephrectomy performed in the presence of severe scoliosis has not been described in the literature before. We report a challenging case of a 13-year-old girl with severe scoliosis requiring a nephrectomy. The feasibility of performing a retroperitoneal laparoscopic nephrectomy in paediatric patients with severe scoliosis is discussed.

What is the effect of circumcision on risk of urinary tract infection in boys with posterior urethral valves?

PURPOSE: Boys with posterior urethral valves (PUV) have increased risks of urinary tract infection (UTI) voiding dysfunction and ongoing renal damage. Circumcision has been shown epidemiologically to reduce UTIs, but no trial has yet confirmed this in PUV. Circumcision is not routinely performed in boys with PUV in our unit, but one quarter of our patients are circumcised for religious reasons. It may be hypothesized that circumcision reduces the risk of subsequent urinary tract infection in boys with PUV. This study aims to test this hypothesis by comparing the risk of UTI, and subsequent renal outcome, in PUV in uncircumcised boys with those who were circumcised. METHODS: A retrospective cross-sectional case note review of boys with PUV was performed, and the following were documented: age at presentation, method of diagnosis, method of treatment, initial renal status, and timing of treatment; use and timing of urinary tract diversion; timing of circumcision; and UTIs-date, organism, and treatment. RESULTS: Seventy-eight patients were identified, mean age 6.7 years (range, 1-18). These boys experienced 78 UTIs in the uncircumcised state. Subsequently, 27 were circumcised, experiencing 8 UTIs. Eighteen boys were diverted. The incidence of UTI was reduced from 0.50 +/- 0.14 (mean +/- SEM) UTIs annually uncircumcised to 0.09 +/- 0.02 (mean +/- SEM) circumcised (P < .01, Student's t test). CONCLUSION: In PUV, circumcision reduces the incidence of UTI by 83%, every circumcision prevents 1 UTI on average. Early circumcision in all PUV is beneficial, but a larger randomised control trial should be considered to confirm this.

Graft-versus-host disease and phimosis.

Graft-versus-host disease rarely causes genitourinary problems. We report a case of pathological phimosis in a child secondary to chronic graft-versus-host disease.

Laparoscopic nephrectomy for xanthogranulomatous pyelonephritis in childhood: the way forward.

OBJECTIVE: Xanthogranulomatous pyelonephritis (XGP) is a severe, chronic renal parenchymal infection. Nephrectomy is curative. Open nephrectomy is a well-known operative challenge. We describe successful laparoscopic nephrectomy in three patients with XGP. MATERIALS AND METHODS: Case notes and radiology of three patients who underwent laparoscopic nephrectomy for XGP were reviewed. The preoperative presentation, operative details, postoperative recovery and complications were recorded. RESULTS: The ages of the three children were 9, 5 and 1.3 years. Retroperitoneoscopy was performed via 3 x 5-mm ports. Creation of retroperitoneal space was easier than anticipated despite the perinephric inflammation. Excellent visualization of renal pedicle was obtained. The renal vessels were divided using the ultrasonic dissector (Sonosurg, Olympus). The kidney was then mobilized and dissected off adjacent structures. It was extracted via a small extension to one of the incisions on each occasion. None of them needed conversion. Average operating time was 3h and 30 min. Histology of XGP was confirmed in all. CONCLUSIONS: Laparoscopic nephrectomy has replaced open nephrectomy for most conditions. Preoperatively, it was thought that laparoscopy might be unsuitable because of the involvement of perinephric tissues commonly seen in this condition; however, excellent visualization was achieved enhancing the ease of dissection. Dealing with the pedicle before handling the kidney also proved beneficial, allowing better visualization and safe dissection. Postoperative pain and morbidity were greatly reduced. The cosmetic result was excellent. We recommend the laparoscopic approach for nephrectomy in XGP when expertise is available.

Laparoscopic excision of Mullerian structures in a neonate with mixed gonadal dysgenesis: a case report.

Excision of Mullerian structures in children with disorders of sexual differentiation is an operative challenge. We report our experience with laparoscopic excision of Mullerian structures in a neonate with mixed gonadal dysgenesis. The salient features of the procedure were excellent visualisation and ease of dissection.

A traumatic intra-renal pseudo-aneurysm in a child.

Intra-renal pseudo-aneurysms after penetrating renal trauma have not been reported in children. We report a case of a 9-year-old girl who presented with gross haematuria 2 weeks following renal exploration for a penetrating injury. The diagnosis of intra-renal pseudoaneurysm was made by Doppler ultrasound and was successfully treated by selective arterial embolisation.

Congenital cystic adenomatoid malformation and extralobar sequestration occurring independently in the ipsilateral hemithorax.

We report a case of congenital cystic adenomatoid malformation (CCAM) and extralobar pulmonary sequestration (EPS) occurring independently in the ipsilateral hemithorax. A literature search using Medline, Winspirs 2.0, found 14 previously reported cases of CCAM within an EPS. There are no reports of each form of congenital pulmonary abnormality occurring separately in the same patient.