Publications by authors named "Imran Mushtaq"

74 Publications

Lower Urinary Tract Symptoms in Adult Females after Feminizing Genitoplasty for Congenital Adrenal Hyperplasia.

J Urol 2020 Dec 21:101097JU0000000000001509. Epub 2020 Dec 21.

Pediatric Surgery and Urology Department, Motol University Hospital, Charles University, Prague, The Czech Republic.

Purpose: To investigate quality of life, long-term lower urinary tract symptoms, sexual function and subjective attitudes towards surgery in adult women after feminizing genitoplasty for congenital adrenal hyperplasia.

Materials And Methods: We retrospectively reviewed the medical files of all patients with congenital adrenal hyperplasia who underwent feminizing genitoplasty from 1996 to 2018 in our tertiary center. Of those, patients older than 16 years of age were asked to answer 1 nonvalidated and 3 standardized and validated questionnaires evaluating their current mental well-being (WHO-5 Well-Being Index), lower urinary tract symptoms (ICIQ-FLUTS) and sexual function (GRISS). The anonymized answers of this cross-sectional study were compared to a control group of 50 healthy females. Student's t-test, Pearson's χ test, Fisher's exact test and Spearman's rank correlation coefficient were performed. A p-value less than 0.05 was considered significant.

Results: Out of 106 patients who underwent feminizing genitoplasty, 64 patients were included and 32 patients, aged 17 to 40 years (median 25.5 years), answered the questionnaires (50% response rate). The difference between congenital adrenal hyperplasia and control group mental well-being was not statistically significant (WHO-5 median score 60 and 64, respectively; p=0.82). We found no significant difference in the lower urinary tract symptoms subscales of filling, voiding or incontinence, nor in the overall lower urinary tract symptoms score (ICIQ-FLUTS overall median score 3.5 and 3, respectively; p=0.43).

Conclusions: We found in our group no abnormal mental well-being or prevalence of long-term symptoms of lower urinary tract dysfunction in adult female patients with congenital adrenal hyperplasia following feminizing genitoplasty.
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http://dx.doi.org/10.1097/JU.0000000000001509DOI Listing
December 2020

The bell-clapper deformity of the testis: The definitive pathological anatomy.

J Pediatr Surg 2020 Jun 25. Epub 2020 Jun 25.

Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. Electronic address:

Introduction: The bell-clapper deformity (BCD) predisposes to intravaginal torsion (IVT) and is classically bilateral. The precise pathological definition of what constitutes a BCD is not clear. The current study aims to clarify the specific anatomic details of this anomaly.

Methods: A systematic review was performed utilizing the PRISMA principles. Studies are presented chronologically based on their level of evidence. They are further divided into study types: autopsy and operative studies of acute torsion, intermittent torsion and studies of the contralateral testis in vanishing testis.

Results: The bell-clapper deformity is best defined by complete investment of the testis, epididymis and a length of the spermatic cord by the tunica vaginalis. Based on autopsy studies the rate of BCD in scrotal testis varied from 4.9% to 16%; with bilaterality in 66%-100%. In cases of acute IVT bilaterality was noted in 54%-100%. The most disparate results were in cases of testicular regression syndrome where contralateral BCD was noted in 0%-87% of cases.

Conclusion: We suggest future studies employ the strict anatomical definition above. As there is evidence of age-dependent investment of the testes, it will be important to develop age-standardized measurements of intravaginal length of spermatic cord. This critical morphometric measurement will allow a better understanding of the risk of IVT.

Level Of Evidence: Systematic review of diagnostic studies: lowest level of evidence of included manuscripts Level IV (case-control studies with a poor reference standard).
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http://dx.doi.org/10.1016/j.jpedsurg.2020.06.023DOI Listing
June 2020

Decreasing Target Behavior in a Child Using Functional Behavior Assessment and Differential Reinforcement.

Indian J Pediatr 2020 06 1;87(6):457-459. Epub 2020 Feb 1.

Department of Clinical Psychology, Faculty of Behavioral Sciences, Shree Guru Gobind Singh Tricentenary University, Gurugram, 122505, India.

Techniques of behavior modification were employed to address the target behavior of functional excessive coughing-psychogenic cough in a 12-y-old boy referred by a pediatrician who found no identifiable medical reasons. To identify the purpose that maintains the behavior, functional behavior assessment was carried out and in order to reduce the frequency of target behavior, extinction and differential reinforcement of behavior analysis was incorporated. The management resulted in significant decrease of the target behavior of coughing without any medical intervention. Behavior modification is the most empirically supported intervention not only for children with developmental delays but for typical individuals as well.
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http://dx.doi.org/10.1007/s12098-020-03192-4DOI Listing
June 2020

Embryonal precursors of Wilms tumor.

Science 2019 12;366(6470):1247-1251

Wellcome Sanger Institute, Hinxton CB10 1SA, UK.

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.
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http://dx.doi.org/10.1126/science.aax1323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914378PMC
December 2019

Spatiotemporal immune zonation of the human kidney.

Science 2019 09;365(6460):1461-1466

Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.

Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly or by cross-talk with immune cells. We used single-cell RNA sequencing to resolve the spatiotemporal immune topology of the human kidney. We reveal anatomically defined expression patterns of immune genes within the epithelial compartment, with antimicrobial peptide transcripts evident in pelvic epithelium in the mature, but not fetal, kidney. A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with postnatal acquisition of transcriptional programs that promote infection-defense capabilities. Epithelial-immune cross-talk orchestrated localization of antibacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection. Overall, our study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge.
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http://dx.doi.org/10.1126/science.aat5031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343525PMC
September 2019

22q11.2 duplications in a UK cohort with bladder exstrophy-epispadias complex.

Am J Med Genet A 2019 03 9;179(3):404-409. Epub 2019 Jan 9.

Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.

The bladder exstrophy-epispadias complex (BEEC) comprises of a spectrum of anterior midline defects, all affecting the lower urinary tract, the external genitalia, and the bony pelvis. In extreme cases, the gastrointestinal tract is also affected. The pathogenesis of BEEC is unclear but chromosomal aberrations have been reported. In particular, duplications of 22q11.2 have been identified in eight unrelated individuals with BEEC. The current study aimed to identify chromosomal copy number variants in BEEC. Analyses was performed using the Affymetrix Genome-wide SNP6.0 assay in 92 unrelated patients cared for by two UK pediatric urology centers. Three individuals had a 22q11.2 duplication, a significantly higher number than that found in a control group of 12,500 individuals with developmental delay who had undergone microarray testing (p < .0001). Sequencing of CRKL, implicated in renal tract malformations in DiGeorge syndrome critical region at 22q11, in 89 individuals with BEEC lacking 22q11 duplications revealed no pathogenic variants. To date, 22q11.2 duplication is the genetic variant most commonly associated with BEEC. This is consistent with the hypothesis that altered expression of a single, yet to be defined, gene therein is critical to the pathogenesis of this potentially devastating congenital disorder.
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http://dx.doi.org/10.1002/ajmg.a.61032DOI Listing
March 2019

Laparoscopic and robotic-assisted repair of retrocaval ureter in children: a multi-institutional comparative study with open repair.

World J Urol 2019 Sep 5;37(9):1941-1947. Epub 2018 Dec 5.

Division of Pediatric Surgery, "Federico II" University of Naples, Via Pansini 5, 80131, Naples, Italy.

Purpose: This retrospective study aimed to report a multi-institutional experience with laparoscopic and robotic-assisted repair of retrocaval ureter in children and to compare outcome of minimally invasive surgery (MIS) with open repair.

Methods: The records of all children, who underwent MIS and open repair of retrocaval ureters in six international pediatric urology units over a 5-year period, were retrospectively collected. Data were grouped according to the operative approach: a laparoscopic group (G1) included five patients, a robotic-assisted group (G2) included four patients, and an open group (G3) included three patients. The groups were compared in regard to operative and postoperative outcomes.

Results: At follow-up, all patients (one G1 patient after redo-surgery) reported complete resolution of symptoms and radiologic improvement of hydronephrosis and obstruction. In regard to postoperative complications, one G1 patient developed stenosis of anastomosis and needed re-operation with no further recurrence (IIIb Clavien). G2 reported the lowest average operative time (135 min) compared to G1 (178.3 min) and G3 (210 min). MIS (G1-G2) reported a significantly better postoperative outcome compared to open repair (G3) in terms of analgesic requirements, hospitalization, and cosmetic results.

Conclusions: The study outcomes suggest that MIS should be the first choice for retrocaval ureter because of the minimal invasiveness and the better cosmetic outcome compared to open surgery. Furthermore, our results showed that robotic-assisted reconstruction was technically easier, safer, and quicker compared to laparoscopic repair, and for these reasons, it should be preferentially adopted, when available.
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http://dx.doi.org/10.1007/s00345-018-2577-zDOI Listing
September 2019

Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors.

Science 2018 08;361(6402):594-599

Wellcome Sanger Institute, Hinxton CB10 1SA, UK.

Messenger RNA encodes cellular function and phenotype. In the context of human cancer, it defines the identities of malignant cells and the diversity of tumor tissue. We studied 72,501 single-cell transcriptomes of human renal tumors and normal tissue from fetal, pediatric, and adult kidneys. We matched childhood Wilms tumor with specific fetal cell types, thus providing evidence for the hypothesis that Wilms tumor cells are aberrant fetal cells. In adult renal cell carcinoma, we identified a canonical cancer transcriptome that matched a little-known subtype of proximal convoluted tubular cell. Analyses of the tumor composition defined cancer-associated normal cells and delineated a complex vascular endothelial growth factor (VEGF) signaling circuit. Our findings reveal the precise cellular identities and compositions of human kidney tumors.
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http://dx.doi.org/10.1126/science.aat1699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104812PMC
August 2018

Distal mesonephric duct anomalies in association with penile ectopia and complex hypospadias.

ANZ J Surg 2019 07 19;89(7-8):965-966. Epub 2018 Jul 19.

Department of Paediatric Urology, Great Ormond Street Hospital for Children NHS Trust, London, UK.

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http://dx.doi.org/10.1111/ans.14379DOI Listing
July 2019

Retroperitoneoscopic partial nephrectomy in children: a multicentric international comparative study between lateral versus prone approach.

Surg Endosc 2019 03 13;33(3):832-839. Epub 2018 Jul 13.

Division of Pediatric Surgery, Federico II University of Naples, Via Pansini 5, 80131, Naples, Italy.

Background: Very limited informations are currently available about the best approach to perform retroperitoneoscopic surgery. This multicentric international study aimed to compare the outcome of lateral versus prone approach for retroperitoneoscopic partial nephrectomy (RPN) in children.

Methods: The records of 164 patients underwent RPN in 7 international centers of pediatric surgery over the last 5 years were retrospectively reviewed. Sixty-one patients (42 girls and 19 boys, average age 3.8 years) were operated using lateral approach (G1), whereas 103 patients (66 girls and 37 boys, average age 3.0 years) underwent prone RPN (G2). The two groups were compared in regard to operative time, postoperative outcome, postoperative complications, and re-operations.

Results: The average operative time was significantly shorter in G2 (99 min) compared to G1 (160 min) (p = 0.001). Only 2 lateral RPN required conversion to open surgery. There was no significant difference between the two groups as for intraoperative complications (G1:2/61, 3.3%; G2:6/103, 5.8%; p = 0.48), postoperative complications (G1:9/61, 14.7%; G2:17/103, 16.5%; p = 0.80), and re-operations (G1:2/61, 3.3%; G2:4/103, 3.8%; p = 0.85). Regarding postoperative complications, the incidence of symptomatic residual distal ureteric stumps (RDUS) was significantly higher in G2 (7/103, 6.8%) compared to G1 (1/61, 1.6%) (p = 0.001). Most re-operations (4/6, 66.6%) were performed to remove a RDUS .

Conclusions: Both lateral and prone approach are feasible and reasonably safe to perform RPN in children but the superiority of one approach over another is not still confirmed. Although prone technique resulted faster compared to lateral approach, the choice of the technique remains dependent on the surgeon's personal preference and experience. Our results would suggest that the lateral approach should be preferred to the prone technique when a longer ureterectomy is required, for example in cases of vesico-ureteral reflux into the affected kidney moiety, in order to avoid to leave a long ureteric stump that could become symptomatic and require a re-intervention.
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http://dx.doi.org/10.1007/s00464-018-6349-zDOI Listing
March 2019

Urethral duplication: a case for careful examination.

Arch Dis Child 2019 Jul 4;104(7):685. Epub 2018 May 4.

Department of Paediatric Urology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1136/archdischild-2018-314830DOI Listing
July 2019

Isolated bilateral simplex ureteric ectopia: Bladder capacity as an indicator of continence outcome.

J Pediatr Urol 2017 Oct 6;13(5):493.e1-493.e9. Epub 2017 Mar 6.

Department of Paediatric Urology, Great Ormond Street Hospital NHS Foundation Trust, London, UK; Departments of Paediatric and Adolescent Urology, University College London Hospitals NHS Foundation Trust, London, UK. Electronic address:

Introduction: Isolated bilateral simplex ectopic ureters (BSEUs) are rare but pose a therapeutic challenge: ureteric reimplantation alone does not accomplish continence in all. Identifying the patients needing additional procedures for continence early could prevent multiple operations.

Objective: Potential preoperative indicators for postoperative continence are explored in eight BSEU girls without cloacal, anorectal, or spinal anomalies.

Study Design: With institutional approval, all patients with BSEU between 1985 and 2012 were retrospectively reviewed. Cystoscopy determined the site of ureteric ectopia (6 of 16 at the bladder neck [BN], 5 of 16 below the BN, and 5 of 16 in the distal urethra). Bladders were assessed by a combination of ultrasound, urodynamics, micturating cystourethrogram, cystoscopic, and intraoperative observations. Expected bladder capacity for age (EBCA) was calculated by 30 ml + (30 ml × age in years) or 38 ml + (2.5 ml × age in months) for children greater or less than 2 years, respectively. Continence outcomes were appraised at a minimum of 4 years. The small number of patients precludes credible statistical analysis and therefore raw data are presented.

Results: Patients underwent cross-trigonal ureteric reimplantation at 1-5.5 years, in five without BN surgery and in three with a Young-Dees-Leadbetter BN tightening. Of those without BN surgery at reimplantation, four achieved satisfactory continence for their age, but one has had multiple procedures culminating in BN closure, ileocystoplasty, and Mitrofanoff. Among the BN-tightening group, one was in nappies at 4 years, one had residual stress incontinence after two further BN injections, and one proceeded to artificial urinary sphincter after two BN injections. Five patients had significant renal impairment.

Discussion: Patients with satisfactory continence after reimplantation alone and those needing further procedures tended to differ in their preoperative observations of bladder capacity and apparent BN competence. This study suggests preoperative observations of an empty bladder on serial ultrasound and/or a wide-open BN with small or even moderate bladder capacity at cystoscopy to indicate the need for BN surgery. In contrast, children with bladder filling to at least 30% of expected bladder capacity for age on preoperative ultrasound or apposition of the BN at cystoscopy may achieve satisfactory continence after ureteric reimplantation alone. Bladder capacity as an indicator of BN competence can also be correlated to continence outcomes in previously published series. Polyuria associated with renal impairment can exacerbate the challenge for continence.

Conclusion: Preoperative bladder capacity appears to be an indicator of inherent BN function and a thorough assessment of the urinary tract by cystoscopy, ultrasound, micturating cystourethrogram, and functional imaging may guide the surgeon on the need for BN surgery at the time of ureteric reimplantation. Where continence remains elusive, patients should be counselled that a further BN injection is occasionally of value although more significant BN procedures are required for most.
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http://dx.doi.org/10.1016/j.jpurol.2016.12.032DOI Listing
October 2017

Single stage urethroplasty for perineal hypospadias in a horse: A case report.

J Pediatr Urol 2017 Feb 9;13(1):84-85. Epub 2016 Nov 9.

Urology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Introduction: Within the veterinary world, data regarding the surgical management of hypospadias is lacking. Reports within equines have documented resective phallectomy procedures rather than urethral reconstruction. This case report documents the first ever urethroplasty for an equine hypospadias, performed by a consultant paediatric surgeon. The urethroplasty was achieved by applying the same surgical principles mastered from paediatric urology to a horse. The indication for surgery was contact dermatitis of the hind-leg, which impaired the thoroughbred foal's racing potential.

Operation: A single stage urethroplasty was performed, during which the wide urethral plate was tubularised in two layers and the urethral meatus was successfully relocated distally to open upon the glans. The urethroplasty was covered with dartos fascia and the penile shaft skin and prepuce were reconstructed. Post-operatively, urine flowed cranially and the contact dermatitis resolved. Minor superficial wound dehiscence was observed which was managed conservatively and self-resolved. Follow-up at 3 years confirmed the horse continues to void from the re-sited meatus without complication and went on to have an illustrious career within horseracing.

Conclusion: We have documented the first reconstructive urethroplasty for hypospadias within a horse, achieved by adopting the surgical techniques normally implemented within paediatric urology with good functionality.
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http://dx.doi.org/10.1016/j.jpurol.2016.09.019DOI Listing
February 2017

Minimally invasive surgery in management of renal tumours in children.

Transl Pediatr 2016 Oct;5(4):305-314

Department of Paediatric Urology, Great Ormond Street Hospital for Children NHS Trust, London, UK.

Minimally invasive surgery (MIS) in the management of malignant and benign renal tumours in children is gradually becoming more common. Experience is limited and restricted to case reports, retrospective chart reviews and a few cohort studies. There are currently no randomized controlled trials or controlled clinical trials comparing the laparoscopic and open surgical approach for the management of renal tumours in children. MIS may offer the same oncologic outcome in malignant renal tumours whilst providing the advantages associated with MIS in correctly selected cases. The technique for tumour resection has been shown to be feasible in regards to the recommended oncologic principles, although lymph node sampling can be inadequate in some cases. Preliminary reports do not show an increased risk of tumour rupture or inferior oncologic outcomes after MIS. However, the sample size remains small and duration of follow-up inadequate to draw any firm conclusions. Implementation of MIS is lacking in the protocols of the major study groups, and standardized recommendations for the indications and contra-indications remain undefined. The objective of this article is to present a review of the literature on the role of MIS in the management of renal tumours in children, with the main focus on Wilms' tumour (WT). Further studies on MIS in renal tumours are required to evaluate the incidence of oncological complications such as complete tumour resection and intra-operative tumour spillage. A long-term follow-up of patients managed by MIS is essential to compare recurrence rates and overall survival rates.
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http://dx.doi.org/10.21037/tp.2016.09.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107380PMC
October 2016

Diagnosis and long-term outcome of renal cysts after laparoscopic partial nephrectomy in children.

BJU Int 2017 05 14;119(5):761-766. Epub 2016 Nov 14.

Department of Paediatric Surgery, Great Ormond Street Hospital, London, UK.

Objective: To document the imaging follow-up of laparoscopic partial nephrectomy (LPN) in children and to investigate the natural history of cystic lesions following LPN.

Patients And Methods: We reviewed the ultrasonography (US) imaging reports performed during the follow-up of 125 children (77 girls, 48 boys; mean age 3.2 years) who underwent LPN in two centres of paediatric surgery in the period 2005-2015.

Results: A transperitoneal approach was adopted in 83 children and a retroperitoneal approach in 42. The mean follow-up was 4.2 years. At US, an avascular cyst related to the operative site was found after 61/125 procedures (48.8%). As for their appearance, 53/61 cysts were simple and anechoic, and eight of the 61 cysts appeared septated. The mean diameter of the cysts was 3.3 × 2.8 cm. As for their course, 13/61 cysts (21.3%) disappeared after a mean of 4 years, 26/61 (42.6%) did not significantly change in dimension, 17/61 (27.8%) decreased in size, and only five of the 61 cysts (8.3%) enlarged. The cysts were asymptomatic in 51 children (83.6%), while they were associated with urinary tract infections (UTIs) and abdominal pain in the remaining 10; none required a re-intervention.

Conclusions: The US finding of a simple cyst at the operative site after LPN is common during follow-up, with an incidence of ~50% in our series. In regard to aetiology, probably a seroma takes the place of the removed hemi-kidney. There was no correlation between cyst formation and type of surgical technique adopted. As there was no correlation between cysts and clinical outcomes, renal cysts after LPN can be managed conservatively, with periodic US evaluations.
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http://dx.doi.org/10.1111/bju.13698DOI Listing
May 2017

Kelly procedure for male primary epispadias.

J Pediatr Urol 2016 Aug 27;12(4):212.e1-2. Epub 2016 May 27.

Great Ormond Street Hospital for Children, Great Ormond Street, London, WC1N 3JH, UK.

Introduction: Primary epispadias is a rare congenital malformation involving the urogenital system. In patients with epispadias, bladder closure enhances bladder growth and continence.

Methods: Several steps were carried out to bring the bladder neck to the midline and allow tension-free bladder neck reconstruction and recreation of the natural angulation of urethra. The urethral plate and penile shaft were dissected and the corpora cavernosa separated, and then the bladder neck repair was performed. The urethral plate was tubularised and brought ventrally. The separated corpora were reapposed, avoiding torsion. The skin was reoriented to provide cover to the penis.

Results: The Kelly procedure improves cosmesis and continence by reconstructing a tension-free bladder neck repair and lengthening the penis.

Conclusion: The video demonstrates the Kelly procedure for primary epispadias in a male child.
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http://dx.doi.org/10.1016/j.jpurol.2016.04.016DOI Listing
August 2016

5 years after an ACE: what happens then?

Pediatr Surg Int 2016 Apr 29;32(4):397-401. Epub 2016 Jan 29.

Department of Paediatric Surgery, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London, UK.

Purpose: Antegrade continence enema (ACE) revolutionised the lives of children with chronic constipation and soiling. Parents often ask how long the ACE will be required. We looked at our patients 5 years after ACE formation to answer the question.

Methods: We reviewed clinical notes of all patients undergoing ACE procedure during January 1990 to December 2010. Only patients with >5 years follow-up were included. Data are given as median (range).

Results: 133 patients were included with >5 years of follow-up. Primary pathology was anorectal anomaly (ARA) 64 (48%); spinal dysraphism (SD) 40 (30%); functional constipation (FC) 14 (10%); Hirschsprung's Disease (HD) 10 (8%) and others 5 (4%). Median follow-up was 7 years (5-17 years). Overall 74% still use their ACE; whilst 26% no longer access their stoma, of whom 47% recovered normal colonic function. 50% of HD patient recover colonic function. FC has the highest failure rate at 21%.

Conclusions: Overall 86% achieved excellent clinical outcome with 74% of patient still using their ACE at 5 years. HD has the highest recovery rate of 50%. FC has a more unreliable clinical outcome with 21% recovered colonic function and 21% failed. Outcome varied dependent on the background diagnosis.
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http://dx.doi.org/10.1007/s00383-016-3857-6DOI Listing
April 2016

Mosaic Activating Mutations in GNA11 and GNAQ Are Associated with Phakomatosis Pigmentovascularis and Extensive Dermal Melanocytosis.

J Invest Dermatol 2016 Apr 14;136(4):770-778. Epub 2016 Jan 14.

Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK; Paediatric Dermatology, Great Ormond Street Hospital for Children, London, UK. Electronic address:

Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Gα subunits of heterotrimeric G proteins. The mutations were detected at very low levels in affected tissues but were undetectable in the blood, indicating that these conditions are postzygotic mosaic disorders. In vitro expression of mutant GNA11(R183C) and GNA11(Q209L) in human cell lines demonstrated activation of the downstream p38 MAPK signaling pathway and the p38, JNK, and ERK pathways, respectively. Transgenic mosaic zebrafish models expressing mutant GNA11(R183C) under promoter mitfa developed extensive dermal melanocytosis recapitulating the human phenotype. Phakomatosis pigmentovascularis and extensive dermal melanocytosis are therefore diagnoses in the group of mosaic heterotrimeric G-protein disorders, joining McCune-Albright and Sturge-Weber syndromes. These findings will allow accurate clinical and molecular diagnosis of this subset of common birthmarks, thereby identifying infants at risk for serious complications, and provide novel therapeutic opportunities.
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http://dx.doi.org/10.1016/j.jid.2015.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803466PMC
April 2016

Phaeochromocytomas and paragangliomas: A difference in disease behaviour and clinical outcomes.

J Surg Oncol 2015 Oct 4;112(5):486-91. Epub 2015 Sep 4.

Centre for Endocrine Surgery, University College London Hospital and Great Ormond Street Hospital, London, UK.

Background: Phaeochromocytomas and paragangliomas arise from the same chromaffin cell, but evidence suggests they do not represent a single clinical entity. The aim of this study was to compare clinical presentations, outcomes of surgical and oncological treatments and survival in patients with phaeochromocytomas and paragangliomas.

Methods: A retrospective review was undertaken of all patients treated for these conditions at our centre between 1983 and 2012.

Results: One hundred and six patients (88 adults, 18 children) with phaeochromocytoma (n = 83) or paraganglioma (n = 23) were studied. Catecholamine symptoms and incidentalomas were the main presentations in phaeochromocytoma patients (67% and 17%) respectively, but in those with paragangliomas pain (39%) was more common (P < 0.001). More paragangliomas were malignant (14/23 vs 9/83, P < 0.0001), larger (9.17 ± 4.95 cm vs. 5.8 ± 3.44 cm, P = 0.001) and had a higher rate of conversion to open surgery (P = <0.01), more R2 resections, more postoperative complications and a longer hospital stay (P = 0.014). MIBG uptake in malignant paragangliomas was lower than in malignant phaeochromocytomas (36% vs. 100%, P = 0.002) and disease stabilisation was achieved in 29% and 86% of patients respectively. (90) Y-DOTA-octreotate had a 78% response rate in malignant paragangliomas.

Conclusion: The clinical differences between paragangliomas and phaeochromocytomas support the view that they should be considered as separate clinical entities.
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http://dx.doi.org/10.1002/jso.24030DOI Listing
October 2015

Environmental Exposure to Endocrine Disruptors: Can We Identify the Link with Genital Disorders?

Eur Urol 2015 Dec 28;68(6):1031-2. Epub 2015 Aug 28.

University College London Hospital, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2015.08.024DOI Listing
December 2015

What is the risk of urinary tract infection in children with antenatally presenting dilating vesico-ureteric reflux?

J Pediatr Urol 2015 Apr 10;11(2):93.e1-6. Epub 2015 Mar 10.

Great Ormond Street Hospital for Children, Great Ormond Street, London, UK. Electronic address:

Introduction: The incidence of recurrent urinary tract infection (UTI) in children with primary vesico-ureteric reflux (VUR) presenting symptomatically is well documented. The risk of UTI in asymptomatic primary VUR diagnosed on investigation of antenatal hydronephrosis (ANH) is less clear. Paradoxically, several previous studies have suggested a lower risk (1-25%). We ascertain the incidence of UTI amongst antenatally-presenting primary VUR and explore risk factors.

Study Design: All patients <16 years managed for primary VUR between 1997 and 2013 were retrospectively reviewed. Patients were identified by searching 'VUR, vesicoureteric reflux' and 'vesico' in the clinical database. Sex, follow up, antibiotic prophylaxis, age at UTI, grade of VUR, radioisotope imaging findings (CRN-congenital reflux nephropathy, NRD-new renal defects), evidence of bladder dysfunction, surgical intervention and resolution were recorded. UTI diagnosis was based on positive urine culture with symptoms including fever. SPSS statistical package and Pearson's Chi-squared test were used to explore significance.

Results: Of 308 patients with primary VUR aged <16 years treated, 242 were diagnosed following presentation with UTI. The remaining 66 (21%) were initially asymptomatic, and VUR was diagnosed on investigation of ANH. All were given prophylaxis from birth. Six months to 16years (median 6years) follow-up was available for 54 (42 males, 12 females). All but two patients had grade III-V VUR (96%), bilaterally in 41 (76%). CRN was evident in 30 (56%; all male) and bladder dysfunction in 12 (22%; 10 males). Twenty-eight patients (52%) developed a UTI. The risk of UTI was 58% in girls, 33% in boys without CRN and 57% in boys with CRN (p = 0.17). Bladder dysfunction was a significant risk factor for UTI (p = 0.03). All 8 (15%; 7 males) with NRD had had a UTI. A single UTI appeared responsible for the majority of NRD (6/8; 75%). UTI occurred in 6/27 (22%) boys after circumcision compared to 17/25 (68%) prior/without circumcision (p < 0.05).

Conclusions: The incidence of UTI in VUR detected after presentation with ANH was 52%. CRN and bladder dysfunction were risk factors for developing a UTI. Circumcision appears to significantly reduce the risk of infection. Antenatal presentation of primary VUR does not carry a reduced risk of UTI. A single UTI, in half before the age of six months, seemed responsible for the majority of NRD. In boys, the highest risk of UTI is in the first few months of infancy, despite antibiotic prophylaxis, and other interventions, particularly circumcision, should therefore be considered as early as possible.
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http://dx.doi.org/10.1016/j.jpurol.2015.01.009DOI Listing
April 2015

Perineal lipoma with accessory labioscrotal fold and penis-like phallus in a female infant with unilateral renal agenesis.

Urology 2014 Jul 22;84(1):209-12. Epub 2014 May 22.

Department of Urology, Great Ormond Street Hospital for Children, London, United Kingdom.

We present a case of a female 46,XX infant with a perineal lipoma within an accessory labioscrotal fold containing a penis-like phallus, associated with contralateral renal agenesis and complete absence of Müllerian/paramesonephric structures. To our knowledge, this is the first report of perineal lipoma and accessory labioscrotal fold associated with urogenital abnormalities in a female. The case also has an exceptional penis-like phallus in the absence of Y chromosome material or evidence of virilization.
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http://dx.doi.org/10.1016/j.urology.2014.03.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4087296PMC
July 2014

Antenatal mild hydronephrosis with subsequent polyp of the upper ureter in a child presenting with recurrent Dietl's crisis.

BMJ Case Rep 2014 May 15;2014. Epub 2014 May 15.

Department of Paediatric Urology, Great Ormond Street Children Hospital NHS Trust, London, UK.

We report a 7-year-old boy who had antenatally diagnosed and postnatally confirmed asymptomatic right congenital hydronephrosis secondary to ureteropelvic junction obstruction with the anteroposterior diameter ranging from 7 to 15 mm on serial ultrasound scans till the age of 6 years. He then presented with recurrent attacks of Dietl's crisis almost every month in the seventh year of his life and eluded diagnosis for over a year at various national hospitals, and ended up with an international referral to us. Investigations of the acute attacks clinched the diagnosis of ureteral polyp causing intermittent crisis and he underwent segmental resection and reconstruction in the form of dismembered Anderson-Hyne pyeloplasty with good recovery. Our case revealed that prenatally detected hydronephrosis may worsen after spontaneous postnatal improvement and a polyp acting as a flip valve may produce intermittent hydronephrosis and symptoms later in life. The child should undergo urgent investigations during acute symptoms.
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http://dx.doi.org/10.1136/bcr-2013-202967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025258PMC
May 2014

Clinical and histopathological features of adrenocortical neoplasms in children: retrospective review from a single specialist center.

J Pediatr Surg 2014 Mar;49(3):410-5

Department of Histopathology, Great Ormond Street Hospital for Children and Institute of Child Health, London WC1N 3JH, UK. Electronic address:

Background/purpose: Adrenocortical tumors (ACTs) are rare in children and the extent to which histopathological features can predict clinical behavior remains uncertain. The aim of this study was to investigate the relationship between histopathological features (Weiss score), surgical approach, tumor size, underlying genetic predisposition syndrome, and outcome.

Methods: Twenty-nine ACTs treated at our institution between 1987 and 2011 were identified from a histopathology database. The histological features were categorized using the Weiss scoring system. For tumor staging, the UKCCSG staging system was utilized.

Results: At a median follow-up of 25 months, 19 patients (65.5%) survived without evidence of disease and 10 patients (35.5%) had died. There was a strong association between high Weiss score and both large tumor size (P<0.01) and adverse outcome (P<0.01). Outcome for stage I and IIA disease was significantly better compared to higher stage disease and/or tumor rupture (P<0.01).

Conclusion: There is an association between high Weiss score, large tumor size, underlying genetic predisposition syndrome and an adverse outcome for pediatric ACTs. Regardless of histopathological findings, complete surgical resection, without tumor spillage, is optimal for survival. Genetic evaluation is recommended in patients with ACTs, particularly those with a high Weiss score.
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http://dx.doi.org/10.1016/j.jpedsurg.2013.09.008DOI Listing
March 2014

Clinical and histopathological features of adrenocortical neoplasms in children: retrospective review from a single specialist center.

J Pediatr Surg 2014 Mar;49(3):410-5

Department of Histopathology, Great Ormond Street Hospital for Children and Institute of Child Health, London WC1N 3JH, UK. Electronic address:

Background/purpose: Adrenocortical tumors (ACTs) are rare in children and the extent to which histopathological features can predict clinical behavior remains uncertain. The aim of this study was to investigate the relationship between histopathological features (Weiss score), surgical approach, tumor size, underlying genetic predisposition syndrome, and outcome.

Methods: Twenty-nine ACTs treated at our institution between 1987 and 2011 were identified from a histopathology database. The histological features were categorized using the Weiss scoring system. For tumor staging, the UKCCSG staging system was utilized.

Results: At a median follow-up of 25 months, 19 patients (65.5%) survived without evidence of disease and 10 patients (35.5%) had died. There was a strong association between high Weiss score and both large tumor size (P<0.01) and adverse outcome (P<0.01). Outcome for stage I and IIA disease was significantly better compared to higher stage disease and/or tumor rupture (P<0.01).

Conclusion: There is an association between high Weiss score, large tumor size, underlying genetic predisposition syndrome and an adverse outcome for pediatric ACTs. Regardless of histopathological findings, complete surgical resection, without tumor spillage, is optimal for survival. Genetic evaluation is recommended in patients with ACTs, particularly those with a high Weiss score.
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http://dx.doi.org/10.1016/j.jpedsurg.2013.09.008DOI Listing
March 2014

Testicular outcome following laparoscopic second stage Fowler-Stephens orchidopexy.

J Pediatr Urol 2014 Feb 31;10(1):186-92. Epub 2013 Aug 31.

Department of Paediatric Urology, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London, UK; Department of Paediatric Urology, University College London Hospitals NHS Foundation Trust, Euston Road, London, UK. Electronic address:

Objective: To assess outcome after laparoscopic second-stage Fowler-Stephens orchidopexy (L2(nd)FSO).

Patients And Methods: Retrospective review of 94 children (aged 0.75-16 years, median 2.75 years), who underwent L2(nd)FSO for 113 intra-abdominal testes between January 2000 and May 2009: 75 unilateral, 19 bilateral (11 synchronous; 8 metachronous). Follow-up (range 3 months-10.9 years, median 2.1 years) was available for 88 children (102 testes: 71 unilateral, 31 bilateral).

Results: Testicular atrophy occurred in 9 out of 102 (8.8%), including 8 out of 71 (11.3%) unilateral and 1 out of 31 (3.2%) bilateral intra-abdominal testes (multivariate analysis: p = 0.59). Testicular ascent ensued in 9 out of 102 (8.8%), comprising four (5.6%) unilateral and five (16.1%) bilateral testicles (multivariate analysis: p = 0.11). Of the 18 bilateral testes brought to the scrotum synchronously none atrophied and four (22.2%) ascended, compared to one (7.7%) atrophy and one (7.7%) ascent among the 13 testes brought to the scrotum on separate occasions (Fisher exact test: p = 0.42 and p = 0.37, respectively). Mobilization of the testis through the conjoint tendon tended towards less ascent (multivariate analysis p = 0.08) but similar atrophy (p = 0.56) compared to mobilization through the deep-ring/inguinal canal. Logistical regression analysis identified no other patient or surgical factors influencing outcome.

Conclusions: This is the largest series of L2(nd)FSO to date. A successful outcome is recorded in 85 out of 102 (83.3%) testicles. Atrophy occurred in 8.8% and ascent in 8.8%.
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http://dx.doi.org/10.1016/j.jpurol.2013.08.005DOI Listing
February 2014

Incidence of Deflux® calcification masquerading as distal ureteric calculi on ultrasound.

J Pediatr Urol 2013 Dec 24;9(6 Pt A):820-4. Epub 2012 Nov 24.

Department of Paediatric Urology, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London WC1N 3JH, UK. Electronic address:

Objective: Dextranomer-hyaluronic acid (Deflux(®)), the most widely used compound in the endoscopic treatment of vesico-ureteric reflux (VUR) today, is believed to provoke only minimal inflammation. Reports of calcification of Deflux(®) are increasing. We ascertain the incidence of Deflux(®) calcification appearing as distal ureteric calculi on ultrasound.

Methods: Three cases (2 external patients) of ureteroscopy for calcified submucosal Deflux(®) prompted a retrospective review of the notes and imaging of all children treated with Deflux(®) for VUR between December 2000 and January 2011 at Great Ormond Street Hospital.

Results: 232 children (M:F = 5:3) received Deflux(®) for VUR at median age 2 years (range 2 months-12 years). Follow-up annual ultrasound, performed in all, identified calcification in 2. The interval between Deflux(®) injection and presentation of its calcification was 4 years. 104 of the 232 children had been followed up for 4-10 years. Considering the observed lag-period, after 4 years the incidence of calcification of Deflux(®) on ultrasound was 2% (2/104).

Conclusions: Patients should be warned that calcification of Deflux(®) can occur. Misinterpretation as ureteric stones is common and may lead to unnecessary ureteroscopy. In this series, the incidence of calcification of Deflux(®) on ultrasound after 4 years was 2%.
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http://dx.doi.org/10.1016/j.jpurol.2012.10.025DOI Listing
December 2013

Penile resurfacing for denuded penis following circumcision.

Pediatr Surg Int 2012 Jun 14;28(6):649-51. Epub 2012 Feb 14.

Great Ormond Street Hospital for Sick Children, London, UK.

Major loss of penile shaft skin following circumcision has been rarely reported in the paediatric literature and when it occurs is usually due to the injudicious use of monopolar diathermy, infection and poor surgical technique. We report the reconstruction of a penis following complete loss of penile skin due to circumcision. We employed a split-skin graft for the glans and full-thickness graft for the shaft to achieve a more natural cosmetic appearance. This approach has not been described previously in the paediatric literature and should be considered in the unfortunate event of significant penile skin loss.
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http://dx.doi.org/10.1007/s00383-012-3057-yDOI Listing
June 2012

Minimally invasive perinatal autopsies using magnetic resonance imaging and endoscopic postmortem examination ("keyhole autopsy"): feasibility and initial experience.

J Matern Fetal Neonatal Med 2012 May 10;25(5):513-8. Epub 2011 Aug 10.

Department of Paediatric Pathology, Clinical Molecular Genetics, Great Ormond Street Hospital for Children and UCL Institute of Child Health, London, UK.

Objective: Perinatal autopsy provides additional diagnostic information in a significant proportion of cases but parents and relatives frequently decline traditional postmortem (PM) examination, partly due to the unacceptability of the cosmetic effects of large incisions and concerns regarding organ retention. We present a novel minimally invasive autopsy method for fetal and neonatal PMexaminations, which includes PM magnetic resonance imaging (MRI) for assessment of anatomy and endoscopic internal examination to allow direct organ visualization and targeted tissue biopsy.

Methods: Descriptive retrospective feasibility report of the first 10 perinatal cases undergoing endoscopic minimally invasive autopsy.

Results: A minimally invasive autopsy (MIA) approach based on postmortem MRI (PM MRI) and endoscopic autopsy with tissue biopsy is feasible and effective with minimal cosmetic consequences compared to traditional PM examination. Endoscopic examination with tissue biopsy provided additional diagnostic information to PM MRI alone in the majority of cases.

Conclusions: Endoscopic MIA is a feasible and potentially more acceptable approach to perinatal autopsy and provides an additional option for parents who do not agree to a traditional PM examination. This approach could result in increased utilization of investigations after death in this group of patients.
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http://dx.doi.org/10.3109/14767058.2011.601368DOI Listing
May 2012