Nathalie Webb

Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort

BackgroundDisorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously.ResultsWe analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management.ConclusionsOur massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.

Unilateral Multicystic Dysplastic Kidney With Progressive Infundibular Stenosis in the Contralateral Kidney: Experience at 1 Center and Review of Literature

PURPOSE We analyzed the association between unilateral multicystic dysplastic kidney and subsequent contralateral infundibular stenosis, which can result in progressive calyceal dilatation, and has been linked to global hyperfiltration injury and renal impairment. MATERIALS AND METHODS During the last 10 years 200 children presented with unilateral multicystic dysplastic kidney. Of these children 5 subsequently exhibited contralateral infundibular stenosis. We reviewed the published data on multicystic dysplastic kidney as well as infundibular stenosis to examine this association further. RESULTS Three patients underwent open surgical exploration since rapid progression with associated parenchymal thinning was detected. Literature review failed to identify any discussion of infundibular stenosis in studies focusing on long-term followup of children with a unilateral multicystic dysplastic kidney. Several case reports and case series discuss this condition in association with other collecting system anomalies. However, these anomalies are hypothesized to be part of a disease spectrum resulting from aberrant formation of the collecting system. Bilateral involvement has been reported in fewer than 10 cases. CONCLUSIONS Our cases represent a part of the spectrum of pyelocalyceal dysgenesis that can have bilateral involvement of varying degrees. Of particular concern was the delayed presentation in some of our patients and the progressive nature of the lesions. Although exceedingly rare, we wish to highlight the association of multicystic dysplastic kidney and progressive infundibular stenosis of the contralateral kidney and renal impairment.

Transitional cell carcinoma in the paediatric population: Be aware of unusual aetiologies

Abstract:  This is a case report of a 12 year old girl who presented with a rare condition in paediatrics, transitional cell carcinoma of the bladder. It is important because it is readily treated by endoscopic means if diagnosed early. Potential aetiologies for this unusual condition are explored.

Disorders of sex development

Disorders of sex development (DSD) are rare, complex anomalies of genital development that often present with an ambiguous genital appearance at birth. Rapid recognition and diagnosis are essential to prevent inappropriate gender assignment in the neonatal ward. After morphological and molecular assessment is complete a management plan is developed by a multidisciplinary team in the tertiary and/or quaternary referral centre.

Simulation in paediatric urology and surgery. Part 1: an overview of educational theory

Surgical training has changed radically in the last few decades. The traditional Halstedian model of time-bound apprenticeship has been replaced with competency-based training. Advanced understanding of mastery learning principles has vastly altered educational methodology in surgical training, in terms of instructional design, delivery of educational content, assessment of learning, and programmatic evaluation. As part of this educational revolution, fundamentals of simulation-based education have been adopted into all levels and aspects of surgical training, requiring an understanding of concepts of fidelity and realism and the impact they have on learning. There are many educational principles and theories that can help clinical teachers understand the way that their trainees learn. In the acquisition of surgical expertise, concepts of mastery learning, deliberate practice, and experiential learning are particularly important. Furthermore, surgical teachers need to understand the principles of effective feedback, which is essential to all forms of skills learning. This article, the first of two papers, presents an overview of relevant learning theory for the busy paediatric surgeon and urologist. Seeking to introduce the concepts underpinning current changes in surgical education and training, providing practical tips to optimise teaching endeavours.

Simulation in paediatric urology and surgery, part 2: An overview of simulation modalities and their applications

Surgical training has changed radically in the last few decades. The traditional Halstedian model of time-bound apprenticeship has been replaced with competency-based training. In our previous article, we presented an overview of learning theory relevant to clinical teaching; a summary for the busy paediatric surgeon and urologist. We introduced the concepts underpinning current changes in surgical education and training. In this next article, we give an overview of the various modalities of surgical simulation, the educational principles that underlie them, and potential applications in clinical practice. These modalities include; open surgical models and trainers, laparoscopic bench trainers, virtual reality trainers, simulated patients and role-play, hybrid simulation, scenario-based simulation, distributed simulation, virtual reality, and online simulation. Specific examples of technology that may be used for these modalities are included but this is not a comprehensive review of all available products.

Evidence-based Treatment of Multicystic Dysplastic Kidney: A Systematic review

OBJECTIVES There is a lack of a standardised protocol for the investigation and non-operative management of paediatric multicystic dysplastic kidney (MCDK). Institutional protocols for non-operative management remain essentially ad hoc. The primary outcome of this systematic review is to establish the incidence of hypertension associated with an MCDK. The secondary outcome is to determine the malignancy risk associated with an MCDK. The tertiary outcome is to assess the rate of MCDK involution. Subsequent to these, an evidence-based algorithm for follow-up is described. METHODOLOGY A systematic review of all relevant studies published between 1968 and April 2017 was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies were identified by specific inclusion and exclusion criteria, all of which included data relevant to the primary, secondary and tertiary outcomes. Hypertension was defined as systolic blood pressure greater than the 95th centile for gender, age and height centile. Subset analysis was performed for hypertension associated with an MCDK. RESULTS The primary outcome measure revealed a 3.2% (27/838) risk of developing hypertension associated with an MCDK. The secondary outcome measure noted a 0.07% malignancy risk (2/2820). The tertiary outcome measure established that 53.3% (1502/2820) had evidence of involution of the dysplastic kidney. A total of 44 cohort studies (2820 patients) were analysed. CONCLUSION Given the low risk of hypertension and malignancy, which is similar to the general population, the current conservative non-operative pathway is an appropriate management strategy. An algorithm to help support clinicians with ongoing management is proposed.

Establishing content validity and fidelity of a novel paediatric intussusception air enema reduction simulator: Novel paediatric intussusception simulator

Intussusception is a common, potentially life‐threatening paediatric condition. Non‐operative treatment with an air enema has been established as the clinical gold standard. There is no validated model for the training of this procedure. Our aim was to produce a novel air enema reduction simulator and validate its use as a training tool.

Multicystic dysplastic kidney and calyceal diverticulum - more of an association than a coincidence?: Letters to the editor

Presacral lesions occupy the presacral space, a potential space bounded by rectum and sacrum. Masses here enlarge into the pelvis or abdominal cavity without causing early compressive symptoms, and often present late because of non-specific symptoms and imaging findings. An unusual case is presented that highlights this diagnostic difficulty. A 46-year-old female was referred following the incidental discovery of a mass during laparoscopic right oophorectomy, which was adherent to the left ovary and rectum (see Fig. 1). There were no remarkable features on examination and tumour markers were normal. Computed tomography (CT) imaging demonstrated a 4-cm presacral mass that did not appear to arise from colon, with softtissue radiographic density. A laparotomy, performed for both diagnosis and treatment, revealed a firm retroperitoneal mass, involving rectum and left ovary. Frozen sections were inconclusive and an anterior resection with en bloc resection was undertaken. Histology demonstrated a mesenteric plexiform neurofibroma. The patient had no other identifiers of neurofibromatosis, was referred to a neurologist and ultimately had an uneventful recovery. This case highlights the diagnostic issues involved in managing presacral masses. Minimal symptoms and inconclusive imaging findings led to a tissue diagnosis at laparotomy being required. There is a broad differential diagnosis, with the most common lesions congenital, comprising teratomas in children and chordomas in adults. Other causes include tailgut cysts, rectal duplication cysts, cystic teratomas and dermoid/epidermoid cysts. Segmental neurofibromatosis presenting as presacral mass has not been widely described. While neurofibromatosis is relatively common, (1 in 3000), segmental neurofibromatosis is much less so (1 in 36,000). Plexiform neurofibromas are pathognomonic for NF1, and represent diffuse neural enlargement. Imaging may be useful to aid management. While plain radiography and ultrasound are non-specific, magnetic resonance and CT show improved diagnostic benefit. These modalities may demonstrate a cystic component, the presence of fat or calcification and relationships to abdominal viscera. Unfortunately, there is a broad spectrum of imaging findings attributable to neurofibromas, and contribute to the low specificity of these scans. This unusual case of a plexiform neurofibroma presenting as a presacral mass demonstrates the difficulties in the investigation and diagnosis of presacral masses. With imaging findings often nonspecific, histological diagnosis and surgical excision may ultimately be required.

Multicystic dysplastic kidney and calyceal diverticulum – more of an association than a coincidence?

Presacral lesions occupy the presacral space, a potential space bounded by rectum and sacrum. Masses here enlarge into the pelvis or abdominal cavity without causing early compressive symptoms, and often present late because of non-specific symptoms and imaging findings. An unusual case is presented that highlights this diagnostic difficulty. A 46-year-old female was referred following the incidental discovery of a mass during laparoscopic right oophorectomy, which was adherent to the left ovary and rectum (see Fig. 1). There were no remarkable features on examination and tumour markers were normal. Computed tomography (CT) imaging demonstrated a 4-cm presacral mass that did not appear to arise from colon, with softtissue radiographic density. A laparotomy, performed for both diagnosis and treatment, revealed a firm retroperitoneal mass, involving rectum and left ovary. Frozen sections were inconclusive and an anterior resection with en bloc resection was undertaken. Histology demonstrated a mesenteric plexiform neurofibroma. The patient had no other identifiers of neurofibromatosis, was referred to a neurologist and ultimately had an uneventful recovery. This case highlights the diagnostic issues involved in managing presacral masses. Minimal symptoms and inconclusive imaging findings led to a tissue diagnosis at laparotomy being required. There is a broad differential diagnosis, with the most common lesions congenital, comprising teratomas in children and chordomas in adults. Other causes include tailgut cysts, rectal duplication cysts, cystic teratomas and dermoid/epidermoid cysts. Segmental neurofibromatosis presenting as presacral mass has not been widely described. While neurofibromatosis is relatively common, (1 in 3000), segmental neurofibromatosis is much less so (1 in 36,000). Plexiform neurofibromas are pathognomonic for NF1, and represent diffuse neural enlargement. Imaging may be useful to aid management. While plain radiography and ultrasound are non-specific, magnetic resonance and CT show improved diagnostic benefit. These modalities may demonstrate a cystic component, the presence of fat or calcification and relationships to abdominal viscera. Unfortunately, there is a broad spectrum of imaging findings attributable to neurofibromas, and contribute to the low specificity of these scans. This unusual case of a plexiform neurofibroma presenting as a presacral mass demonstrates the difficulties in the investigation and diagnosis of presacral masses. With imaging findings often nonspecific, histological diagnosis and surgical excision may ultimately be required.