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Andrology Sep 2020Genitourinary anomalies occur in approximately 1% of humans, but in most cases, the cause is unknown. Aristaless-like homeobox 4 (ALX4) is an important homeodomain...
BACKGROUND
Genitourinary anomalies occur in approximately 1% of humans, but in most cases, the cause is unknown. Aristaless-like homeobox 4 (ALX4) is an important homeodomain transcription factor. ALX4 mutations in humans and mouse have been associated with craniofacial defects and genitourinary anomalies such as cryptorchidism and epispadias.
OBJECTIVES
To investigate the presence and the functional impact of ALX4 variants in patients with genitourinary defects.
MATERIALS AND METHODS
Two separate patient cohorts were analyzed. One includes clinical exome-sequencing (ES) data from 7500 individuals. The other includes 52 ALX4 Sanger-sequenced individuals with bladder exstrophy-epispadias complex (BEEC). Dual luciferase assays were conducted to investigate the functional transcriptional impact of ALX4 variants in HeLa cells and HEK293 cells.
RESULTS
A total of 41 distinct ALX4 heterozygous missense variants were identified in the ES cohort with 15 variants present as recurrent in multiple patients. p.G369E and p.L373F were the only two present in individuals with genitourinary defects. A p.L373F heterozygous variant was also identified in one of the 52 individuals in the BEEC cohort. p.L373F and p.G369E were tested in vitro as both are considered damaging by MutationTaster, although only p.G369E was considered damaging by PolyPhen-2. p.L373F did not alter transcriptional activity in HeLa and HEK293 cells. p.G369E caused a significant 3.4- and 1.8-fold decrease in transcriptional activities relative to wild-type ALX4 in HEK293 and HeLa cells, respectively.
DISCUSSION AND CONCLUSIONS
Our study supports the idea that transcription factors like ALX4 could influence the normal development of the GU tract in humans as demonstrated in mouse models as ALX4 variant p.G369E (predicted pathogenic by multiple databases) affects ALX4 function in vitro. Variant p.L373F (predicted pathogenic by only MutationTaster) did not affect ALX4 function in vitro. Exon-sequence information and mouse genetics provide important insights into the complex mechanisms driving genitourinary defects allowing the association of transcriptional defects with congenital disorders.
Topics: DNA-Binding Proteins; Genetic Variation; HEK293 Cells; HeLa Cells; Humans; Transcription Factors; Urogenital Abnormalities
PubMed: 32385972
DOI: 10.1111/andr.12815 -
International Journal of Surgery Case... Nov 2021Bladder exstrophy is a rare congenital anomaly while, bladder adenocarcinoma mucinous type is a rare type of bladder cancer, with aggressive behavior and inadequate...
INTRODUCTION
Bladder exstrophy is a rare congenital anomaly while, bladder adenocarcinoma mucinous type is a rare type of bladder cancer, with aggressive behavior and inadequate response to radiation and chemotherapy. In extremely rare cases, untreated bladder exstrophy could transform into bladder mucinous adenocarcinoma.
CASE PRESENTATION
We report a case of a 41-year-old male with untreated bladder exstrophy that transformed into mucinous adenocarcinoma. The patient also had epispadias and a right inguinal hernia. Joint procedures were conducted to perform radical cystectomy, total penectomy and W-Pouch continent urostomy, inguinal hernia repair, osteotomy, and keystone and scrotal flap by split-thickness skin graft (STSG) for wound closure. The patient progressed well after surgery, two months after initial procedure, nephrostomies were conducted due to pouches stenosis. Due to the government's limited transportation and lockdown policy, as the Covid-19 pandemic occurred, the patient could not come to the hospital for routine follow-up and died nine-month after surgery.
CLINICAL DISCUSSION
Bladder exstrophy is one of the risk factors of bladder cancer. Transformation of bladder exstrophy into mucinous adenocarcinoma is extremely rare, as the case is the first case to be discovered in Indonesia. Surgery, followed with a strict follow-up regime, is mainstay of treatment in this type of malignancy.
CONCLUSION
Adenocarcinoma of mucinous type is a scarce type of bladder exstrophy malignancies. A multidiscipline approach is mandatory in these cases. Strict and regular follow up are suggested for these cases.
PubMed: 34717273
DOI: 10.1016/j.ijscr.2021.106493 -
JBJS Essential Surgical Techniques Mar 2019Bladder exstrophy is a congenital condition that affects the genitourinary and musculoskeletal systems, and less commonly affects the intestinal system, with cloacal...
BACKGROUND
Bladder exstrophy is a congenital condition that affects the genitourinary and musculoskeletal systems, and less commonly affects the intestinal system, with cloacal exstrophy. This condition results from abnormal migration of the mesenchyme, between the endoderm and ectoderm, leading to anterior rupture of the cloacal membrane. Numerous osseous morphologic changes are observed in bladder exstrophy. Rotational anomalies include external rotation of the posterior part of the pelvis and iliac wings, on average 12°, and acetabular retroversion. Although various osteotomy types have been described for initial bladder exstrophy closure, the anterior approach has demonstrated positive outcomes in improving daytime continence, gait, and correction of the diastasis. Thus, the anterior iliac osteotomy provides an effective method to help close the pelvic ring and decrease stress on the anterior abdominal wall during exstrophy closure. In addition, this technique promotes continence by reconfiguring, and thereby restoring, the fibrous symphyseal bar and pelvic floor musculature.
DESCRIPTION
The steps of the procedure include (1) preoperative planning, (2) patient positioning, (3) incision, (4) identification of the lateral femoral cutaneous nerve, (5) subperiosteal dissection of the iliac wing, (6) guide pin placement and anterior osteotomy, (7) posterior hinge osteotomy (for cloacal exstrophy and for patients ≥2 years old), (8) external fixator pin placement, (9) anterior internal fixation of the pubic symphysis (for cloacal exstrophy and for patients ≥2 years old), and (10) resumption of the urologic procedure followed by wound closure and application of external fixator.
ALTERNATIVES
Numerous previous techniques for osteotomies in bladder exstrophy have been developed, starting with Shultz in 1958, who recognized the importance of bringing the pubic bones together for gait correction in exstrophy repair. O'Phelan was the first, to our knowledge, to document outcomes of this bilateral posterior osteotomy technique to reduce tension from the externally rotated iliac bones and widened pubic symphysis in a 2-stage bladder exstrophy closure. Other approaches have included an oblique iliac wing osteotomy and pubic ramotomy, described by Frey and Cohen in 1989. However, the latter approach inadequately restores the pelvic osseous relations except in female newborns who would have a small diastasis after manual rotation of the pelvis.
RATIONALE
This procedure has several advantages over the prior conventional posterior approach. These include better approximation and improved mobility of the pubic rami at the time of closure, prevention of vertical migration of the hemipelvis, direct visual placement of an external fixator and adjustment postoperatively, and no requirement for turning the patient during the operation. In addition, this procedure allows for adjunctive posterior osteotomy from the anterior approach to provide adequate closure in those with cloacal exstrophy, prior failed closure, or extreme diastasis of >6 cm.
PubMed: 31086719
DOI: 10.2106/JBJS.ST.18.00018 -
Frontiers in Pediatrics 2019
PubMed: 31482079
DOI: 10.3389/fped.2019.00349 -
BMC Urology Aug 2022To represent the long-term outcomes of our modified single-stage technique for the reconstruction of isolated penopubic epispadias in male patients.
OBJECTIVE
To represent the long-term outcomes of our modified single-stage technique for the reconstruction of isolated penopubic epispadias in male patients.
PATIENTS AND METHODS
Data from 113 patients were obtained from bladder-exstrophy-epispadias database of our tertiary center. A total of seven boys with isolated penopubic epispadias with no prior history of surgery and any other anomaly underwent our modified surgical approach from February 1997 to September 2019. The mean ± SD age at surgery was 6.5 ± 2.4 years. Volitional voiding status and cosmetic appearance were evaluated at each follow-up interval. Postoperative follow-up was performed at quarterly intervals in the first year and once a year in subsequent years.
RESULTS
The mean ± SD of follow-up was 8.5 ± 6 years. All boys who were incontinent achieved urinary control and the ability of normal transurethral micturition following the surgery. Four boys became completely dry, and the other three attained social dryness. Postoperative mean (SD) bladder capacity was significantly increased from 54.5 (11) to 124 (40.0) within 6 months, and to 194 (47.5) at 18 months after surgery. Dorsal curvature has been resolved in all cases, and no postoperative complications were noted except for surgical site infection in one patient treated with antibiotics and bilateral vesicourethral reflux resolved after injection of bulking agents. Four patients had normal erectile function and ejaculation, while the others have not reached puberty yet. Moreover, none of the patients developed urethrocutaneous fistula, stricture, or penile ischemia.
CONCLUSION
The present findings suggest the safety and effectiveness of the combination of single-stage urethro-genitoplasty, bladder neck plication, and fat pad pedicled flap in management of boys with isolated penopubic epispadias that can lead to the achievement of urinary control, acceptable sexual function, and cosmetically satisfactory genitalia. Minimal morbidity, low complication rate, and promising outcomes are essential factors, supporting the notion of introducing this technique as a valid option for management of this entity.
Topics: Bladder Exstrophy; Epispadias; Humans; Male; Penis; Treatment Outcome; Urethra
PubMed: 36038905
DOI: 10.1186/s12894-022-01089-2 -
Indian Journal of Pathology &... Nov 2023Bladder exstrophy is a rare congenital anomaly in which the urinary bladder develops outside the body. It may be part of the bladder epispadias-exstrophy-cloacal...
Bladder exstrophy is a rare congenital anomaly in which the urinary bladder develops outside the body. It may be part of the bladder epispadias-exstrophy-cloacal complex, which is a serious embryological defect where a spectrum of abnormalities involving the urinary tract, genital tract, musculoskeletal system, and intestinal tract is seen. Primary signet ring cell adenocarcinoma (PSRCA) arising in exstrophy of the urinary bladder is extremely rare with only a few cases reported in the literature. A 32-year-old man with congenital, untreated bladder exstrophy presented with a large fungating mass on the lower abdominal wall. Physical examination revealed a 15 × 12 cm exophytic mass with a penile epispadias. Ultrasonography showed a replacement of the urinary bladder by a mass of size 9 × 8 × 7 cm with a defect in the abdominal wall. On Contrast-enhanced computed tomography (CECT), a mass protruding from a large, inferior abdominal wall defect of 5.3 cm was seen. Widened pubic symphysis with divarication of recti and an absent urinary bladder, consistent with bladder exstrophy, was also noted. The biopsy showed a signet ring cell adenocarcinoma. A radical cystectomy with ileal conduit and left inguinal lymph node dissection was done. Histopathology examination revealed a PSRCA with metastasis to the left inguinal lymph nodes. Immunohistochemistry (IHC) showed strong positivity with CDX2 and CK20 while CK7 was negative. PSRCA shows an aggressive behavior, as was seen in our case, which had metastatic inguinal lymph nodes at the time of presentation. Metastatic signet ring cell adenocarcinomas from other sites need to be ruled out. Bladder exstrophy can develop high-grade malignancies at any stage of life. Hence, surgical treatment early in life with lifelong follow-up is recommended.
PubMed: 38394437
DOI: 10.4103/ijpm.ijpm_1025_22 -
Journal of the American Veterinary... Mar 2018CASE DESCRIPTION A 14-week-old 7.7-kg (16.9-lb) sexually intact female Golden Retriever was evaluated because of urine dripping from the caudoventral aspect of the...
CASE DESCRIPTION A 14-week-old 7.7-kg (16.9-lb) sexually intact female Golden Retriever was evaluated because of urine dripping from the caudoventral aspect of the abdomen. CLINICAL FINDINGS Ultrasonography, radiography, excretory CT urography, and vaginocystourethroscopy were performed. Results indicated eversion of the bladder through the ventral abdominal wall with exposure of the ureterovesicular junctions, pubic diastasis, and an open vulva and clitoral fossa. Clinical findings were suggestive of bladder exstrophy, a rare congenital anomaly. TREATMENT AND OUTCOME The dog was anesthetized and bilateral ileal osteotomies were performed. Two ureteral catheters were passed retrograde into the renal pelves under fluoroscopic guidance. The lateral margins of the bladder, bladder neck, and urethra were surgically separated from the abdominal wall, and the bladder was closed, forming a hollow viscus. The symphysis pubis was closed on midline with horizontal mattress sutures. The defects in the vestibule and clitoral fossa were closed. Lastly, the iliac osteotomies were stabilized. The dog was initially incontinent with right hind limb sciatic neuropraxia and developed pyelonephritis. Over time, the dog became continent with full return to orthopedic and neurologic function, but had recurrent urinary tract infections, developed renal azotemia likely associated with chronic pyelonephritis, and ultimately was euthanized 3.5 years after surgery because of end-stage kidney disease. CLINICAL RELEVANCE Bladder exstrophy and epispadias is a treatable but rare congenital abnormality. The procedure described could be considered for treatment of this condition, but care should be taken to monitor for urinary tract infections and ascending pyelonephritis.
Topics: Animals; Bladder Exstrophy; Dog Diseases; Dogs; Endoscopy; Epispadias; Fatal Outcome; Female; Osteotomy; Plastic Surgery Procedures; Tomography, X-Ray Computed
PubMed: 29504860
DOI: 10.2460/javma.252.6.732 -
Communications Biology Nov 2022Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer...
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.
Topics: Humans; Animals; Mice; Bladder Exstrophy; Genome-Wide Association Study; Urinary Bladder Neoplasms; Transcriptome; Ephrin-A1
PubMed: 36352089
DOI: 10.1038/s42003-022-04092-3 -
Pediatric Reports Apr 2021The term exstrophy-epispadias complex refers to a group of midline defects ranging from epispadias to cloacal exstrophy. Bladder exstrophy is the most frequent...
The term exstrophy-epispadias complex refers to a group of midline defects ranging from epispadias to cloacal exstrophy. Bladder exstrophy is the most frequent malformation of this spectrum and it can present as a classical or a variant form. We report a case of a hybrid bladder exstrophy variant having some characteristics of both a duplicate bladder exstrophy and a superior vesical fistula.
PubMed: 33916945
DOI: 10.3390/pediatric13020024 -
Journal of Pediatric Urology Jun 2023Despite the proliferation of over 45 000 smartphone mobile health applications (MHAs), as far as we know, there is no MHA for those living with rare diseases such as...
GOALS
Despite the proliferation of over 45 000 smartphone mobile health applications (MHAs), as far as we know, there is no MHA for those living with rare diseases such as Bladder Exstrophy-Epispadias-Cloacal Exstrophy complex (BEEC). We hypothesized that an MHA could provide similar "on-demand" information and connectivity within health communities for patients with BEEC as they do for more common diseases. Thus, our primary goal was to create an MHA for patients and families affected by BEEC to provide them with important information about the condition and a format for them to connect with other affected patients and families. A secondary goal was to develop an adaptable MHA template for other rare diseases in the future.
METHODS
We began our app development by examining existing common-disease MHAs for thematic structure. We conducted an extensive literature search of PubMed and Google scholar for MHA development and existing MHAs related to BEEC, utilizing these search terms: mobile health applications, rare diseases, bladder exstrophy, and online health communities. Our app development team began with our clinical multidisciplinary team of pediatric urologists; a child psychiatrist; a patient/family mental health therapist; and a certified nurse practitioner. We hired a website engineer and a production team. All clinical members have extensive experience caring for children and families affected by BEEC. Additionally, clinical team members compiled lists of themes deemed relevant from these reviews and themes gleaned from their clinical experience that appear with some frequency or urgency and from the myriad of themes discussed within the literature for MHAs.
RESULTS
We found no existing rare disease MHAs in the literature or our search of app stores online. However, we derived basic app categories from existing MHA formats and the thematic content of all sources reviewed. These categories aligned with the groupings of our lists of clinical themes. Thus, we could subsume diverse themes within a broad categorical format: for example, child development (as "Psychological Development" in the app) or various clinical care options (as "Treatment"). This app structure became nine sections, as shown in. This format allows diverse information to be retrieved efficiently from broader categories. This app is being offered to affected families, healthcare providers, and individuals unrelated to where care is offered.
CONCLUSION
"We the BE" is the first MHA developed for a rare disease, BEEC. It has been published in a downloadable format for the general public at no cost. Further research is required to determine its efficacy for the BEEC community members; preliminary, unsolicited feedback from multiple users has been positive.
Topics: Humans; Child; Bladder Exstrophy; Epispadias; Rare Diseases; Mobile Applications
PubMed: 36959037
DOI: 10.1016/j.jpurol.2023.02.021