Epispadias

Etiology

Epispadias represents the least severe form of the ECC, which is composed of several similar, related congenital malformations characterized by an anterior abdominal wall defect along with various types and degrees of genitourinary abnormalities.[1] In epispadias, the abdominal wall defect is associated with an open urethral plate in males or a cleft in females.[1] When associated with an evaginated bladder, this becomes bladder exstrophy. Isolated epispadias constitutes <10% of the total number of cases of this disorder.[3] Within the ECC, a multitude of systems may be involved, including urinary, musculoskeletal, pelvic, pelvic floor, abdominal wall, genitalia, spine, and rectum. Epispadias represents the least severe form of the ECC.[1]

Genetic, developmental, and environmental factors are thought to play a role in the etiology of the ECC, although the actual underlying cause is not known.[1] Various animal models have also suggested that interactions between genetic growth and transcription factors may play a role in its occurrence.[4]

The etiology of the ECC involves embryological disturbances involving the cloacal membrane during the early stages of development. Persistence of the cloacal membrane without the usual ingrowth of the reinforcing middle mesodermal layer leads to early rupture and a wide spectrum of congenital anomalies of the ECC, depending on the timing and severity of the premature event.[5][6]

Embryological, this involves the following: [6]

• The cloacal membrane consists of an ectodermal and endodermal layer at the caudal end of the early abdominal wall's germinal disk. A mesenchymal layer normally inserts itself between the 2 layers of the cloacal membrane during gestational weeks 4 and 5, ultimately helping to form the lower abdominal muscles and pelvic bones.

• The new, triple-layered cloacal membrane then fuses with the descending urorectal septum, which subsequently perforates and separates into the hindgut and the urogenital sinus at about gestational week 6. 

• Premature perforation of the cloacal membrane, caused by the lack of timely development of the mesenchymal layer, is a result of the weakness and instability of the structure without its normal reinforcing mesenchymal layer.[1][5]

• The precise cause of the failure of the mesenchymal layer support is still unclear, but it may be due to an unusually thick, overdeveloped, or adherent bilaminar cloacal membrane.[6]

• When the cloacal membrane ruptures prematurely, the result is 1 of the EEC congenital anomalies, with cloacal exstrophy representing the earliest, most severe defect and epispadias the latest and mildest.[1][5] 

• The earlier the rupture, the more complex the resulting anomaly.

• As a result, a spectrum of anomalies can present (the earlier in development the rupture, the more complex the anomaly). These include (in increasing order of severity) epispadias, classic bladder exstrophy, and cloacal exstrophy.[1]

• A rupture of the cloacal membrane before fusion with the urorectal septum results in cloacal exstrophy with externalization of the combined lower urinary and distal gastrointestinal tracts.[7] 

• If the rupture occurs after this fusion, the result is classical bladder exstrophy.[7]

• Isolated epispadias represents a late disruption of the cloacal membrane, causing a nonunion of the most distal portion of the urinary tract. It can present as a more focal distal defect or occur more proximally, where it can impact the urinary sphincter and bladder.[8] 

Other theories include abnormal development of the bony pelvis that blocks or delays the normal midline alignment of the pelvic organs, genital tubercle malposition, early midline fusion posterior to the cloacal membrane, or any mesenchymal abnormality that prevents normal tissue migration and integration with the cloacal membrane.[6][9][10][11][12][13][14]

Epidemiology

Epispadias is a rare, sporadic, congenital birth defect with an estimated worldwide incidence of 2.4 in 100,000 live births, according to the International Clearinghouse for Birth Defects Monitoring Systems.[6][15][16] The condition is more common in males than females, with an estimated 1.4:1 ratio, but the incidence in girls is likely grossly underestimated due to the difficulty in diagnosis.[6][15][16] The incidence of isolated epispadias is 1 in 100,000-160,000 in males to 1 in 480,000 in females.[2][17] The highest reported rate of 8.1 per 100,000 live births is reported in Native Americans, while 1 of the lowest rates was in Asian Americans, with only 1 case per 100,000 live births.[1]

The risk factors for epispadias are similar to those of other forms of EEC, including lack of prenatal care, smoking, and possibly advanced parental age. No additional risk factors for epispadias are known. Compliance with periconceptional folate supplementation reduces the risk of severe forms of the spectrum of EEC, but the risk of occurrence of milder forms, such as epispadias, is not decreased.[17][18]

Pathophysiology

The features and pathophysiology encountered in epispadias are variable and are likely associated with the timeline of embryologic dysfunction. Earlier perturbment yields more proximal and severe anomalies, whereas later disruption results in a milder form of the malformation. About 20% to 50% of epispadias patients will have vesicoureteral reflux compared to close to 100% in bladder exstrophy patients.[19][20]

Epispadias in males is categorized into glanular, penile, or penopubic forms depending on the location of the ectopic dorsal urethral meatus. Urinary incontinence is almost always seen in the penopubic form due to an associated incompetent bladder neck. The most common and severe presentation of epispadias is the most severe penopubic form (70%).[21] Features of isolated epispadias in males include a short phallus, an abnormal dorsally located urethral meatus, dorsal chordee, and a ventrally hooded prepuce with the dorsal portion absent.

Until recently, it was believed that the degree of incontinence depended only on the position of the meatus, with distal (glanular) epispadias not being associated with incontinence. However, histological abnormalities within the roof of the urethra concurrent with a more distal meatus have shown that there are additional factors determining continence in these patients.[22] 

Epispadias in females can be categorized into vestibular (mild), sub-symphyseal (intermediate), and retro-symphyseal (severe) types.[1] A patulous urethral meatus is seen only in the vestibular (milder) forms. The retrosymphyseal form can present with complete incontinence and an extremely small bladder capacity.[23] More severe forms may demonstrate a urethral cleft involving the bladder neck with prolapse of the vesicle mucosa.[1] 

History and Physical

Epispadias is often apparent at birth, and the initial diagnosis does not usually require additional investigation except for associated anomalies. In males, the inner lining of the urethra lies flat, open, and exposed on the skin just below the pubic bone. In females and males with glanular epispadias, the condition may be difficult to diagnose from a casual inspection, requiring a careful, focused examination of the external genitalia. The diagnosis can be easily missed if the child is continent. Glanular epispadias is sometimes identified at the time of circumcision when the foreskin is retracted. 

Epispadias in females also poses a diagnostic challenge. Due to the rarity of the disease, it is often noticed only on focal perineal examination that may not be performed until the patient is being evaluated for delayed toilet training or some other reason.[24] Sometimes, the initial diagnosis may be delayed until school age or even later, especially in females, if it is not associated with incontinence. On occasion, these anomalies are diagnosed in the prenatal period secondary to atypical ultrasound findings, such as difficulty visualizing the bladder and/or genitalia, failure of bladder filling, low umbilical insertion, or an abdominal wall mass.

Urinary incontinence in isolated epispadias can be variable. In males, it was originally thought to depend only on the position of the meatus; the majority of children with penopubic defects are incontinent due to involvement of the bladder neck, but cases of incontinence in distal epispadias suggest additional factors contributing to the failure of the continence mechanism. In females, incontinence is a typical finding.[24][25] 

The anatomy of the abdominal wall, rectus musculature, umbilicus, and testes are completely normal in epispadias. The pubic symphysis may be normal or demonstrate only a small gap in EEC-related epispadias. Larger gaps will be found in exstrophy, male patients with incontinence, and in isolated epispadias. The widening of the pubic symphysis is caused by the external rotation of the innominate pelvic bones. The penopubic ligaments are therefore tightened with lateral displacement and distortion, resulting in a short penis with dorsal chordee and curvature.

Examination of the male external genitalia will demonstrate a short phallus with a dorsal meatus, dorsal chordee (bend), and ventrally hooded prepuce. The total corporal length is short due to the foreshortened anterior corporal segment (the posterior segment is normal). Splaying and shortening of the corpora and the pubic diastasis are responsible for the short penile length. 

• Other factors contributing to the smaller appearance of the phallus include the short urethral plate and dorsal chordee. 

• The vas and ejaculatory ducts are normal, but these structures are at risk of being injured during reconstruction.[25] 

Examination of young females with epispadias will reveal a bifid clitoris, anteriorly placed vaginal orifice, absent mons, laterally displaced small labia minora, and a patulous urethral orifice, possibly with a visible bladder neck or even mucosal prolapse in more severe cases.[25] When associated as a part of the ECC, other clinical abnormalities may also be present and are generally apparent on physical examination.

Evaluation

The diagnosis of epispadias is based on the clinical examination. However, further workup is generally warranted, given the frequency of associated anomalies. A complete physical exam should be performed upon diagnosis of epispadias. If sacral dimpling is noted, a spinal ultrasound, CT, or MRI should be performed to assess for tethering.

A plain radiograph should always be performed to assess for pubic diastasis. It is recommended that a radiopaque ruler be placed in a position that will be visible on the x-ray without obscuring the pubic bones, such as on the lower abdomen or the upper thighs. An ultrasound to assess for associated congenital anomalies of the upper tract is often performed in children with incontinent epispadias as part of the preoperative evaluation. If there is any question, a pelvic MRI will give the most precise anatomical information on soft tissue structures in the pelvis. Other functional studies, including VCUG and nuclear scintigraphy scans, should be performed to assess baseline renal function, particularly prior to any reconstructive surgery.[24] The incidence of vesicoureteric reflux in epispadias ranges from 35% to 85% due to ureteral ectopia. In general, the greater the degree of bladder neck involvement and incontinence, the higher the likelihood of finding vesicoureteral reflux.

Before any surgical intervention of the epispadias, the presence or absence of dry periods without incontinence should be documented. The absence of such dry periods suggests bladder-neck dysfunction. Other studies to evaluate the activity and functionality of the bladder neck would include VCUG, urodynamics, and cystoscopy. 

Treatment / Management

Surgical treatment of epispadias is technically challenging. It is difficult to achieve significant surgical experience in repairs outside of tertiary care referral centers of excellence as the condition is so uncommon. For these reasons, referral of patients to such centers is highly recommended. Goals include correcting the dorsal chordee, reconstructing the glans and urethra, lengthening and transposing the corpora, and creating optimal cosmesis while preserving the blood supply and avoiding any injury to associated normal structures such as the vas. An optimal outcome would include good cosmetic appearance, continence, normal sexual performance with preserved fertility, and adequate penile length. In experienced hands, most epispadias patients have good, acceptable outcomes after genital reconstructive surgery, with the majority reporting a straight penis with normal sexual function and fertility. When bladder neck surgery is required, reported continence rates are about 80%.[1]

Surgical repairs of epispadias are generally done when the child is at least 1 year of age or older to minimize the anesthesia risk, although some recommend it be done earlier at age 6 to 12 months. There is no urgent or emergent need for surgery in newborns. It is recommended that the procedure be performed before the age of toilet training.[6] 

Surgical approaches can be divided into staged versus complete repair. For isolated epispadias, the repair is often accomplished within a single procedure. When repairing a more extensive exstrophy, the urethral and genital reconstruction often occurs in conjunction with bladder neck repair and bilateral ureteral reimplantations (subsequent bladder neck surgical modifications may be required in patients with persistent urinary incontinence). 

All epispadias repairs must deal with 4 issues as follows: [1] 

1. Correction of the dorsal chordee and curvature
2. Dissection of the corpora, transposition, and lengthening them by medial rotation, if possible, or by incision and anastomosis
3. Urethral reconstruction for urination and ejaculation
4. Reconstruction of the glans

There are several described surgical techniques, but the 2 most common approaches are discussed below.

The modified Cantwell-Ransley repair involves partial penile reconstruction with urethral repositioning.[1] It begins with releasing the chordee through mobilization of the urethral plate, extending from the underlying corpora to the glans and the prostatic urethra, followed by tubularization with the advancement of the urethral meatus.[24][25] The corpora spongiosa and urethral plate are completely mobilized, which allows the urethra to be more easily transposed ventral to the corpora cavernosa.[24][25][26] Lateral rotation of the corpora then helps further correct the dorsal penile curvature.[1] The corporal bodies are medially rotated, approximated, and connected over the repaired urethra, which can generally be done without mobilization of the delicate neurovascular bundles unless corporal incisions and anastomoses are required.[26] A reverse meatal advancement and glanuloplasty complete the procedure.[1]

The Mitchell repair requires complete penile disassembly and reconstruction.[27] First described in 1996, it is based on the unique vascular anatomy of epispadias which allows for complete separation of the urethral plate, the corpora. In epispadias, each corpora cavernosum and its associated hemiglans has its own separate nerve and vascular supply on the dorsal lateral corporal surface. Therefore, the corpora can be dissected free as each has its own dorsal artery, deep cavernosal artery, and neurovascular bundle.[27] In the Mitchell procedure, the urethral plate is completely dissected from the corpora and hemiglans, and the corporal bodies are completely separated from each other.[27] Note that the urethral plate receives its supply from the corpora spongiosa, and extensive dissection is discouraged as it may lead to ischemia. The reconstructed urethra is repositioned ventrally, covered by the corpora.[27] Malrotation of the corpora contributing to any dorsal curvature is corrected.[27] The surgery is completed with a reverse meatal advancement and glanuloplasty procedure.

The Mitchell repair offers several theoretical advantages: [25][27]

• The complete disassembly of the penis optimizes ventral positioning.
• The entire distal urethra can easily undergo tubular reconstruction. 
• Repair of the glans and urethra can be done separately.
• The 2 halves of the glans and the corpora are completely separate, facilitating the release of any undue rotation causing dorsal penile curvature.
• Dorsal chordee and curvature are corrected more effectively.
• Optimizes exposure for any additional surgery, such as dermal grafts.
• Allows for an easy extension to a bladder neck reconstruction if necessary.
• It optimizes penis length, although this is somewhat debatable.

Complete penile disassembly with the Mitchell repair may yield better reconstruction than the Cantwell-Ransley technique. Another advantage is that the dissection extends to the bladder neck, and if indicated, a bladder neck repair can be easily added during the procedure.[25] The success of the reconstruction is based on tissue integrity as well as the surgeon's skill level and experience. The main disadvantage is the increased risk of vascular compromise and potentially catastrophic complications such as ischemia of the glans or corporal necrosis.[21] It also requires more aggressive dissection and has a higher incidence of hypospadias as a complication.[28] The reconstructed urethra is often short, resulting in a hypospadias urethral meatus which may require further surgery to reach the tip of the penis. A modified single-stage procedure that includes a fat pad pedicled flap recently reported good results in a small number of penopubic epispadias patients.[21]

Repair of epispadias in females follows similar surgical principles but is generally less complicated than male reconstruction. It is traditionally done as a 2-stage surgery using the Young-Dees-Leadbetter technique or, more recently, by a single-stage approach.[29][30][31][32] The selection of a particular procedure depends on the clinical situation, the need for ureteral reimplantation, and the surgeon's preference, skill, and experience. For example, a purely perineal approach is not advantageous if ureteral reimplantations are required. A description of 1 technique includes the following:(B3)

• The urethra and bladder neck are mobilized along with the vagina using a perineal approach. 

• Division of the intersymphyseal bands is crucial to ensure the completeness of the posterolateral dissection.

• Exposure of the pelvic floor muscle complex marks the completion of the posterior dissection.

• The mobilized urethra is then tubularized over a self-retaining Foley catheter. The neourethra and vagina are shifted posteriorly. If necessary, the pubic bones are approximated, or osteotomies can be done.

• Clitoroplasty and labioplasty are performed later or simultaneously.[25] This is accomplished by excising the small, triangular area just anterior to the clitoris and then closing the wound lengthwise. This will fuse the bifid clitoris and the labia. The bifid clitoris is sometimes left untouched to minimize any potential damage to its nerve supply. 

• Skin and inguinal tissue adjacent to an abnormal-appearing mons pubis can be partially dissected and rotated medially to fill any gaps, depressions, or denuded areas or correct any retraction involving the mons.[1]

In the setting of a patulous bladder neck, the traditional staged approach is generally preferred, involving a urethroplasty followed by bladder neck reconfiguration at a later date. A high rate of urinary continence is achieved when epispadias repair and bladder neck reconfiguration are performed successively at 12 to 18 months and 5 to 6 years of age, respectively.[33] 

Reconstruction of the bladder neck, if necessary, is usually postponed until the bladder capacity exceeds at least 60 mL, but 100 mL or more is preferred for best results. (The 100 mL bladder capacity is typically achieved by age 5 years.) The child needs to actively participate in continence training. The preoperative bladder capacity is a strong predictor of postoperative continence. A modified Young-Dees-Leadbetter bladder neck reconstruction procedure is generally the procedure of choice as it protects the neurological supply to the bladder.[1] When bladder neck reconstruction is needed and performed due to incontinence, bilateral ureteral reimplantations (antireflux procedures) are typically done simultaneously as the 2 conditions (vesicoureteral reflux and incompetent bladder neck) occur together so frequently.[1]  Most patients with penopubic epispadias will ultimately need at least 1 bladder neck procedure to become continent. Even patients with less severe glanular or penile epispadias may need such procedures, as the degree of the epispadias does not always correlate well with continence.[34][35][36](B3)

Differential Diagnosis

Epispadias represents the mildest manifestation of the EEC but may be present within the setting of more severe exstrophy involving the bladder and/or gastrointestinal structures. Pubic diastasis is common with bladder exstrophy, cloacal exstrophy, and isolated epispadias. The most severe form of EEC is cloacal exstrophy. In this condition, often diagnosed prenatally, both the genitourinary and gastrointestinal systems are impacted as the pathology is due to the failure of these pathways to differentiate fully. Cloacal exstrophy is characterized by the presence of major anomalies, including an omphalocele (with malrotation), a split phallus (with 2 halves), bladder exstrophy (with 2 bladder halves separated by a strip of cecum), a prolapsed segment of ileum, an imperforate anus, widened pubic symphysis (diastasis), and spinal abnormalities.[7] 

Bladder exstrophy is identified by similar but less severe anomalies involving these same organs.[37]

• The pelvic contents, such as the bladder, rectum, urethra, and vagina, are displaced anteriorly.                             
• There is pubic diastasis with foreshortened anterior pelvic bones. There is external rotation of the anterior and posterior pelvic bones.[38]                         
• The bladder is externalized and prolapsed on the anterior abdominal wall. The extent of the prolapse may range from just the trigone to the entire bladder.   
• The ureteral orifices are typically visible.                                                                                                          
• The rectal opening will be ectopic anteriorly, and some patients will have a patulous anus.                                        
• In females, the vaginal opening will be displaced anteriorly, and the clitoris will be divided or bifid. Duplications of the vagina and/or uterus may be present.     
• In males, the penis is stubby and short with a dorsal chordee.
  • The glans will appear crushed or flat with separated corpora.
  • The testes may be undescended.
  • Bilateral inguinal hernias may also be present.

Hypospadias is another presentation of a congenital distal urethral anomaly in males but is not involved in EEC, which features a ventral meatus, ventral chordee, dorsally hooded prepuce, and lacks pubic diastasis.[39] Penile length is usually normal.[39]

Common urogenital sinus, a disorder of sexual differentiation, is frequently misdiagnosed as epispadias in girls. The patulous urethral opening may appear to be a single opening in the vestibule. However, focal examination reveals the anteriorly placed vaginal opening.

Prognosis

The goals of epispadias repairs include urinary continence, acceptable cosmesis, and normal sexual function. Variable rates of continence, ranging from 50% to 90%, have been cited by surgical centers worldwide.[17][25]  In boys, continence depends in part on the type of epispadias; an abnormal proximal urethra and incompetent bladder neck are almost always associated with penopubic defects. In girls, the continence rates after surgery for epispadias are also variable, ranging between 60% and 80% for daytime continence. For both, nocturnal continence rates are <50%.[23]

Important components of surgical intervention are restoration of normal appearing genitalia and preservation of sexual function. There are variable reports (primarily in males) of satisfaction with appearance and sexual function as well as fertility after genital reconstructive surgery for epispadias, but the majority of patients are reasonably satisfied. Many of these patients require monitoring throughout adulthood to screen for any decrement in upper urinary tract function (as a consequence of, for example, bladder outlet obstruction).

Complications

Factors influencing complication rates include tissue integrity, the need for multiple interventions, the extent of anomalous anatomy, and surgical expertise. A urethrocutaneous fistula is the most common complication of epispadias surgery and will occur in 13% to 18% of all cases.[6][40][41]

Surgical complications include the following: 

• Ischemia issues: Catastrophic complications can occur, particularly with the Mitchell-Bagli technique of complete penile disassembly, resulting in necrosis of the glans, corpora, or other structures.                             
• Persistent chordee: This can be addressed or avoided by performing cavernostomies before medializing and reapproximating the corporal bodies.     
• Persistent short penile length: Releasing the corporal bodies, dividing the intersymphyseal bands, and advancing the dissection to the bladder neck can provide additional length.                                                       
• Partial or complete penile loss: Cases, where penile loss occurs postoperatively, can be attributed to a rare anomalous vascular distribution in addition to the generally tenuous blood supply in newborns.                                           
• Tight urethral plate closure: Closing the open urethral plate too tightly may overly increase outlet resistance and possibly lead to upper genitourinary tract damage.                                                                      
• Urethral retraction and hypospadias: A urethral plate shortage may be encountered during complete penile disassembly. In these scenarios, some surgeons perform a distal preputial tube urethroplasty.                               
• Urethral stricture and obstruction: Improper tissue handling and vascular compromise can lead to the formation of strictures. These can be managed by dilatation but may occasionally require urethral substitution.                                                                                                                                                     
• Vesicocutaneous fistula: A fistula between the bladder and the skin is a common complication following the initial closure of the bladder.                       
• Wound complications: Complex and multiple surgeries lead to tissue scarring, diminished elasticity, and reduced vascularity. With each subsequent surgery, the tissue is at a greater risk for ischemia, resulting in suboptimal healing and further complications.[42][6][24][25]