Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia.

INTRODUCTION: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development. METHODS: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal. RESULTS: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants. CONCLUSION: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.

Surgical Management of Neurogenic Sphincter Incompetence in Children.

We report on the results of a literature review regarding the indications and results of operations to increase bladder outlet resistance to achieve dryness in children with neurogenic sphincter incompetence (NSBD). The relative advantages and disadvantages of injection of bulking agents, periurethral slings, bladder neck reconfiguration, artificial sphincters, and bladder neck closure based on a literature review and our combined clinical experience are discussed. Based on this review and our experience, we propose that periurethral injection of bulking agents is not justified as a primary treatment. Likewise, operations that reconfigure the bladder neck are not very useful since most patients also require bladder augmentation and an abdominal catheterizable channel. Bladder neck slings with autologous tissues are effective, mostly in females bur in the majority of patients a bladder augmentation is necessary. There is a role also for implantation of artificial urinary sphincters but when done as an isolated procedure, close monitoring to detect possible detrusor changes is needed. Bladder neck closure is an effective measure when other methods have failed.

Should CAH in Females Be Classified as DSD?

Great controversies and misunderstandings have developed around the relatively recently coined term disorders of sex development (DSD). In this article, we question the wisdom of including XX individuals with congenital adrenal hyperplasia (CAH) in the DSD category and develop arguments against it based on the published literature on the subject. It is clear that females with CAH assigned the female gender before 24 months of age and properly managed retain the female gender identity regardless of the Prader grade. Females with CAH and low Prader grades have the potential for a normal sexual and reproductive life. Those with greater degrees of prenatal androgen exposure (Prader grades IV and V) raised as females also identify themselves as females but experience more male-like behavior in childhood, have a greater rate of homosexuality, and have greater difficulty with vaginal penetration and maintaining pregnancies. Improvement in surgical techniques, better endocrinological, psychological, and surgical follow-up may lessen these problems in the future. Given the fact that the term DSD includes many conditions with problematic gender identity and conflicts with the gender assigned at birth, it may be appropriate to exclude females with CAH from the DSD classification.

Alternatives to conventional enterocystoplasty in children: a critical review of urodynamic outcomes.

Alternatives to conventional enterocystoplasty have been developed in order to avoid the most common complications derived from contact of the urine with intestinal mucosa. In this article critically we review the literature on the topics: ureterocystoplasty, detrusorectomy, detrusorotomy, seromuscular gastroenterocystoplasty, use of off the shelf biomaterials, and bladder augmentation by bioengineering. Recognizing the difficulty of deciding when a child with a history of posterior urethral valves requires and augmentation and that the development of a large megaureter in cases of neurogenic dysfunction represents a failure of initial treatment, we conclude that ureterocystoplasty can be useful in selected cases when a large dilated ureter is available. Seromuscular colocystoplasty lined with urothelium (SCLU) has been urodynamically effective in several series when the outlet resistance is high and no additional intravesical procedures are necessary. Seromuscular gastrocystoplasty lined with urothelium seems to offer no distinct advantages and involves a much more involved operation. The use of seromuscular segments without urothelial preservation, with or without the use of an intravesical balloon has been reported as successful in two centers but strict urodynamic evidence of its effectiveness is lacking. The published evidence argues strongly against the use of detrusorectomy or detrusorotomy alone because of the lack of significant urodynamic benefits. Two recent reports discourage the use of small intestinal submucosa patches because of a high failure rate. Finally, research into the development of a bioengineered bladder constructed with cell harvested from the same patient continues but is fraught with technical and conceptual problems. In conclusion of the methods reviewed, only ureterocystoplasty and SCLU have been proven urodynamically effective and reproducible.

The Surgical Correction of Urogenital Sinus in Patients with DSD: 15 Years after Description of Total Urogenital Mobilization in Children.

Total urogenital sinus mobilization has been applied to the surgical correction of virilized females and has mostly replaced older techniques. Concerns have been raised about the effect of this operation on urinary continence. Here we review the literature on this topic since the description of the technique 15 years ago. Technical aspects and correct nomenclature are discussed. We emphasize that the term "total" refers to an en-bloc dissection and not to the extent of the proximal dissection. No cases of urinary incontinence have been reported following this operation. It is yet too early to evaluate results regarding sexual function but it is likely that the use of a posterior skin flap to augment the introitus will minimize the development of introital stenosis.

Importance of urinary flow studies after hypospadias repair: a systematic review.

A systematic review was performed of publications relating to the results of urinary flow studies after hypospadias repair dating back to 1978, when what appears to be the first publication on this topic was found. The literature search was performed using the key words "hypospadias" combined with "urinary flow", "urine flow", "uroflow", "uroflowmetry", and "long-term". We also reviewed the abstracts and full-length articles cited in the reference list of selected articles. Criteria for inclusion in the present systematic review included descriptions of patient selection, surgical technique, the severity of disease (proximal vs distal), and the method used to determine uroflow, as well as a definition of urethral obstruction. In all, 339 article titles were found. Of these, 25 abstracts appeared relevant and the full text of these articles were reviewed, with 22 of the papers included in this review. Sixteen reports had appeared in the literature since 2001, compared with six between 1978 and 2000, suggesting an increasing interest in this topic. On the basis of the results of the present systematic review, we recommend that asymptomatic children operated on for hypospadias in infancy should have one flow study after toilet training, with that study repeated if the results are abnormal. It appears that early abnormal flows improve spontaneously, so that children operated on after toilet training who are asymptomatic should undergo their first uroflow measurement 1 year after surgery. Children with obstructed flow parameters or borderline flows should be followed until adulthood, until long-term follow up studies clarify the significance of abnormal flow parameters. Given the present findings, we anticipate that in the next two decades urologists will need to treat a number of men with strictures resulting from hypospadias repairs performed in childhood.

[The treatment of vesicoureteral reflux in children with myelomeningocele]. / Tratamiento del reflujo vesicoureteral en niños con mielomeningocele.

OBJECTIVES: To perform a bibliographic review on the topic of vesicoureteral reflux (VUR) in children with myelomeningocele. METHODS: PubMed search using the terms: vesicoureteral reflux and myelomeningocele. RESULTS: Between 1981 and 2007 340 articles were found, 61 of which were considered adequate, and 48 were used as references for this monographic issue. We discuss the pathogenesis of VUR in neurogenic bladder, the efficacy of conservative treatment with clean intermittent catheterization and anticholinergic drugs, as well as the indications and efficacy of various surgical procedures including ureteral reimplantation, subureteral injection of various agents, bladder augmentation, cutaneous vesicostomy, urethral dilation, transureteral-ureterostomy and botulin toxin injection. CONCLUSIONS: Vesicoureteral reflux plays an important role in the development of renal damage in infants and children with congenital myelomeningocele. Nephropathy may be prevented with adequate evaluation and follow-up and timely therapeutic intervention. Renal failure in these patients always reflects the failure of medical care or social/socioeconomic conditions.

Tratamiento del reflujo vesicoureteral en niños con mielomeningocele / The treatment of vesicoureteral reflux in children with myelomeningocele

Objetivo: Hacer una revisión de la literatura sobre el tópico de reflujo vesicoureteral (RVU) en niños con mielomeningocele. Métodos: Búsqueda en PubMed bajo los títulos: vesicoureteral reflux y myelomemingocele. Resultados: Entre 1981 y 2007 se encontraron 340 artículos de los cuales 61 se consideraron pertinentes y 48 se usaron como referencias para esta mononografía. Se discute la patogénesis del RVU en la vejiga neurógena, la efectividad del tratamiento conservador con cateterismo intermitente y anticolinérgicos, así como la indicación y efectividad de diversos procedimientos quirúrgicos incluyendo el reimplante ureteral, la inyección subureteral de varios agentes, la ampliación vesical, vesicostomía cutánea, dilatación uretral, transuretero-ureterostomía e inyección de toxina botulínica. Conclusión: El RVU juega un papel importante en el desarrollo de daño renal en infantes y niños nacidos con mielomeningocele. La nefropatía puede ser prevenida con una evaluación y seguimiento adecuados y con intervención terapéutica oportuna. La insuficiencia renal en estos pacientes siempre refleja el fracaso de la atención médica o de las condiciones sociales o socio-económicas (AU)

Objectives: To perform a bibliographic review on the topic of vesicoureteral reflux (VUR) in children with myelomeningocele. Methods: PubMed search using the terms: vesicoureteral reflux and myelomeningocele. Results: Between 1981 and 2007 340 articles were found, 61 of which were considered adequate, and 48 were used as references for this monographic issue. We discuss the pathogenesis of VUR in neurogenic bladder, the efficacy of conservative treatment with clean intermittent catheterization and anticholinergic drugs, as well as the indications and efficacy of various surgical procedures including ureteral reimplantation, subureteral injection of various agents, bladder augmentation, cutaneous vesicostomy, urethral dilation, transureteral-ureterostomy and botulin toxin injection. Conclusions: Vesicoureteral reflux plays an important role in the development of renal damage in infants and children with congenital myelomeningocele. Nephropathy may be prevented with adequate evaluation and follow-up and timely therapeutic intervention. Renal failure in these patients always reflects the failure of medical care or social/socioeconomic conditions (AU)