Expanding the <em>HPSE2</em> Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder

Copyright \ua9 2022 Beaman, Lopes, Hofmann, Roesch, Promm, Bijlsma, Patel, Akinci, Burgu, Knijnenburg, Ho, Aufschlaeger, Dathe, Voelckel, Cohen, Yue, Stuart, Mckenzie, Elvin, Roberts, Woolf and Newman. Urofacial (also called Ochoa) syndrome (UFS) is an autosomal recessive congenital disorder of the urinary bladder featuring voiding dysfunction and a grimace upon smiling. Biallelic variants in HPSE2, coding for the secreted protein heparanase-2, are described in around half of families genetically studied. Hpse2 mutant mice have aberrant bladder nerves. We sought to expand the genotypic spectrum of UFS and make insights into its pathobiology. Sanger sequencing, next generation sequencing and microarray analysis were performed in four previously unreported families with urinary tract disease and grimacing. In one, the proband had kidney failure and was homozygous for the previously described pathogenic variant c.429T&gt;A, p.(Tyr143*). Three other families each carried a different novel HPSE2 variant. One had homozygous triplication of exons 8 and 9; another had homozygous deletion of exon 4; and another carried a novel c.419C&gt;G variant encoding the missense p.Pro140Arg in trans with c.1099-1G&gt;A, a previously reported pathogenic splice variant. Expressing the missense heparanase-2 variant in vitro showed that it was secreted as normal, suggesting that 140Arg has aberrant functionality after secretion. Bladder autonomic neurons emanate from pelvic ganglia where resident neural cell bodies derive from migrating neural crest cells. We demonstrated that, in normal human embryos, neuronal precursors near the developing hindgut and lower urinary tract were positive for both heparanase-2 and leucine rich repeats and immunoglobulin like domains 2 (LRIG2). Indeed, biallelic variants of LRIG2 have been implicated in rare UFS families. The study expands the genotypic spectrum in HPSE2 in UFS and supports a developmental neuronal pathobiology

Treatment Strategies and Outcome of the Exstrophy–Epispadias Complex in Germany: Data From the German CURE-Net

Introduction: To evaluate the impact of reconstructive strategies and post-operative management on short- and long-term surgical outcome and complications of classical bladder exstrophy (CBE) patients' comprehensive data of the multicenter German-wide Network for Congenital Uro-Rectal malformations (CURE-Net) were analyzed. Methods: Descriptive analyses were performed between 34 prospectively collected CBE patients born since 2009, median 3 months old [interquartile range (IQR), 2–4 months], and 113 cross-sectional patients, median 12 years old (IQR, 6–21 years). Results: The majority of included individuals were males (67%). Sixty-eight percent of the prospectively observed and 53% of the cross-sectional patients were reconstructed using a staged approach (p = 0.17). Although prospectively observed patients were operated on at a younger age, the post-operative management did not significantly change in the years before and after 2009. Solely, in prospectively observed patients, peridural catheters were used significantly more often (p = 0.017). Blood transfusions were significantly more frequent in males (p = 0.002). Only half of all CBE individuals underwent inguinal hernia repair. Cross-sectional patients after single-stage reconstructions showed more direct post-operative complications such as upper urinary tract dilatations (p = 0.0021) or urinary tract infections (p = 0.023), but not more frequent renal function impairment compared to patients after the staged approach (p = 0.42). Continence outcomes were not significantly different between the concepts (p = 0.51). Self-reported continence data showed that the majority of the included CBE patients was intermittent or continuous incontinent. Furthermore, subsequent consecutive augmentations and catheterizable stomata did not significantly differ between the two operative approaches. Urinary diversions were only reported after the staged concept. Conclusions: In this German multicenter study, a trend toward the staged concept was observed. While single-stage approaches tended to have initially more complications such as renal dilatation or urinary tract infections, additional surgery such as augmentations and stomata appeared to be similar after staged and single-stage reconstructions in the long term

A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy

Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer susceptibility. Previous genetic studies identified one locus to be involved in classic bladder exstrophy, but were limited to a restrict number of cohort. Here we show the largest classic bladder exstrophy genome-wide association analysis to date where we identify eight genome-wide significant loci, seven of which are novel. In these regions reside ten coding and four non-coding genes. Among the coding genes is EFNA1, strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequence of EFNA1 in the investigated classic bladder exstrophy cohort of our study displays an enrichment of rare protein altering variants. We show that all coding genes are expressed and/or significantly regulated in both mouse and human embryonic developmental bladder stages. Furthermore, nine of the coding genes residing in the regions of genome-wide significance are differentially expressed in bladder cancers. Our data suggest genetic drivers for classic bladder exstrophy, as well as a possible role for these drivers to relevant bladder cancer susceptibility.A genome-wide association study on classic bladder exstrophy reveals eight genome-wide significant loci, most of which contained genes expressed in embryonic developmental bladder stages.Deutsche Forschungsgemeinschaft (German Research Foundation) https://doi.org/10.13039/50110000165

Zirkumzision und Orchidopexie

Circumcision and orchidopexy are among the most frequently performed pediatric urological procedures. Although they may be classified as surgical interventions suitable for junior surgeons, either procedure can lead to serious consequences including the loss of the respective organ. In this paper, the general aspects of pediatric urological surgery (e.g., distinctive features of informing underage patients, the handling of children in the operating room, and relevant pediatric anesthesiological aspects) are described first. Then, the most important sources of error will be highlighted and potential complications and their management during all stages of the procedure will be illustrated. Apart from the so-called freehand circumcision, this paper also deals with potential complications when using the PlastibellA (R) device. In regard to orchidopexy, laparoscopic procedure shall be discussed in addition to the standard procedure

Blasenekstrophie

It is universally agreed that successful and gentle initial bladder closure is decisive for favorable long-term outcome. Due to a number of reasons, including a lack of comparable multicenter studies, there are numerous concepts for initial exstrophy closure. Therefore, we describe our concept of delayed, staged reconstruction without osteotomy in classical bladder exstrophy, while taking into considerion the available literature on long-term follow-up as well as on own clinical and research data. Most notably there are multiple medical but also psychological advantages of a delayed procedure. Primary closure without osteotomy is feasible and has no disadvantages in the long-term follow-up when compared to the invasive procedure of osteotomy. Due to high intravesical pressure, initial bladder neck surgery might have negative effects on bladder development and on the upper urinary tract

Lichen sclerosus im Kindesalter

Lichen sclerosus (LS) is a chronic inflammatory disease of the skin. It mainly affects the anogenital area. More knowledge of the disease is needed to avoid delay in diagnosis as early treatment may cure the disease in some and reduce or prevent scarring. Initial treatment for girls and boys comprises the daily application of a potent cortisone ointment for 3 months. After remission the treatment should be continued long-term intermittently. If there is no complete remission in boys complete circumcision is recommended. LS usually cannot be healed but only well suppressed, and also after circumcision recurrences may occur years later. Therefore, patients have to be well informed and should be followed up long-term

Intraskrotales Lipoblastom im Kindesalter

Based on a case report of an intrascrotal lipoblastoma in childhood, we present the pre-operative diagnostic algorithm and the main differential diagnoses in testicular and paratesticular tumors as well as their surgical management. An 8-week-old infant was admitted with a scrotal tumor known since birth. MRI showed a pinnate vessel supply, originating in the left internal iliac artery. The tumor was exposed operatively and could be completely removed. Intrascrotal lipoblastoma are rare. Like most testicular and paratesticular tumors in childhood lipoblastomas are benign. Today ultrasound and Doppler sonography are basic tools for diagnosis and surgical planning in testicular and scrotal tumors in childhood. In some cases MRI can provide additional important information for surgical planning. In contrast to adults testis sparing surgery is favoured in children

Acquired cryptorchidism: More harm than thought?

Introduction Acquired cryptorchidism (AC) has been recognized as a subgroup of undescended testes (UDT). There is growing evidence that the compromising effect equals that of congenital UDT (cUDT). This prospective study included an extensive histological examination of biopsies taken from AC patients. Patients and methods From August 2013 to December 2014, 21 boys (3-12 years of age) underwent testicular biopsy during orchiopexy for AC. Patient and family histories were taken. The amount of germ cells ( GC) per tubule (T) and the amount of adult dark spermatogonia (Ad-S) per T were determined by resin semi-thin sections examination. The samples were also scanned for signs of malformation. Immunohistochemical stains were performed as markers for atypical germ cells. Results Four (19%) boys were born prematurely, two (9.5%) were small for gestational age (SGA), and nine (43%) had a positive family history of UDT. The median of GC/T was 1.06 in boys = 9 years. The median of Ad-S/T was 0.02 in boys = 9 years. There were no signs for malformation and no atypical cells. The immunohistochemical stains were negative in all specimens. Conclusions Prematurity, SGA, and a positive family history appeared to be predictors for AC. Extensive histopathological examination of AC revealed a significant reduction of germ cell count and fertility markers, comparable with that in cUDT. The alterations were more severe in boys aged >= 9 years. It is unclear as to whether or not this was possibly caused by a longer duration of inguinal position, but this finding suggests that routine checks of testicular position throughout childhood are needed, and that there is a cause for continued efforts in educating parents and primary care physicians regarding AC. Current data support the notion of surgical correction once the diagnosis is made