Cloacal Exstrophy

Cloacal exstrophy is a rare congenital disorder that may be related to the abnormal development of the cloacal membrane which results in in an abdominal wall defect and failed closure of the lower urinary tract. It has been referred to as the OEIS (omphalocele, exstrophy, imperforate anus and spinal defect) complex (1), although all of these anomalies are not always present. (2) The exstrophy, epispadias (EES) complex has also been described, though it is less commonly utilized. The classic presentation of EES includes two exstrophied bladder halves, an exstrophied hindgut, and an imperforate anus. Omphalocele is present in more than 60% of cases, though it is not essential for diagnosis. Associated anomalies are numerous and include gastrointestinal anomalies, central nervous system anomalies, renal and cardiac anomalies, and limb defects.

1. Q64 Other congenital malformations of urinary system
   1. Q64.0 Epispadias
   2. Q64.1 Exstrophy of urinary bladder
      1. Q64.12 Cloacal exstrophy of urinary bladder
   3. Q64.8 Other specified congenital malformations of urinary system
   4. Q64.9 Congenital malformation of urinary system, unspecified

Historically, the incidence of OEIS has been reported as 1 in 200,000-400,000 live births. However, the pregnancy incidence may be higher due to lack of diagnosis in stillborn infants. (3, 4) A higher incidence has been reported in multiple gestations, and it may be more common in monozygotic twins than dizygotic twins. (5, 6) In addition, a higher incidence has been reported in pregnancies resulting from assisted reproductive technology. (7)

Currently, it is not clear whether cloacal exstrophy is a distinct entity or part of a continuum that includes bladder exstrophy, epispadias, and the urorectal-septal malformation sequence. (2, 9-11) In this section, we present a review of normal embryogenesis and potential developmental theories about the cloacal exstrophy/OEIS complex.

In normal embryogenesis, before the 5^th week of gestation, the urinary, genital and gastrointestinal tracts empty into a common cavity, the cloaca. The cloacal membrane lies at the caudal end of the germinal disk and forms the ventral wall of the urogenital sinus. (12, 13) Between days 5 and 19, the cloacal membrane connects the genital tubercle to the tail portion of the embryo inferiorly, and is obliterated in all other locations. During this time, mesoderm migrates to form the inferior abdominal muscles and public bones. (13) By the end of the first month, the extraembryonic mesoderm of the proximal vitelline duct and the allantois fuse to form the urorectal septum. (14, 15) The urorectal septum continues to grow caudally and passively separates the posterior alimentary system (hindgut) from the anterior urogenital system (bladder). (16) This process is complete when the urogenital septum comes in close contact proximity with the cloacal membrane, (17) and remnants of the cloacal membrane are converted to the urogenital and anal membranes, which eventually dehisce and allow for the establishment of urogenital and anal orifices. (15, 17, 18)

There are numerous points in embryogenesis at which abnormal development may lead to various gastrointestinal and/or urinary anomalies. For example, abnormal mesodermal migration between the ectodermal and endodermal layers of the cloacal membrane can cause premature cloacal rupture; if the cloacal membrane ruptures before the urorectal septum has separated the hindgut from the bladder, cloacal exstrophy can occur, and if the rupture occurs following the formation of the urorectal septum, exstrophy may be limited to the bladder. Other theories for the pathogenesis of cloacal exstrophy include abnormal development of the caudal cloaca preventing mesenchymal tissue migration, abnormal fusion of the genital tubercle below the cloacal membrane, and abnormally caudal position of body stalk and failure of mesenchymal ingrowth. (18-20)

In addition to the above possible etiologies of cloacal exstrophy, several genetic defects have also been implicated in the pathogenesis, including an unbalanced translocation between the long arm of chromosome 9 and the Y chromosome (9q34.1-qter deletion) (21), mutations in homeobox genes (HLXB9 and HOX family genes) (22), and chromosome 1p36 deletion (23). Additionally, there have been reports of OEIS complex in cases of trisomy 18. (1)

Numerous anomalies can be associated with cloacal exstrophy/OEIS complex. Associated spinal and central nervous system anomalies occur in 30-70% of cases and include hemivertebrae, meningomyelocele, spinal dysraphism, spina bifida, hydrocephalus, and Arnold Chiari malformations. (4, 24) Gastrointestinal defects can involve other abdominal wall defects including omphalocele, intestinal malrotation, bowel duplication, Meckel diverticulum, duodenal atresia, and imperforate anus. (1, 4) Urinary tract defects occur in 60% of cases and include dysplastic kidneys, pelvic kidneys, and hydronephrosis. (3) Clubbed feet occur in 20-40% of cases. (4) In addition, cardiac anomalies, oligohydramnios/polyhydramnios, and single umbilical arteries have also been associated with cloacal exstrophy/OEIS complex. (18, 24)

Antenatal diagnosis relies heavily on imaging; historically, OEIS has been diagnosed during the second trimester anatomy survey. First trimester diagnosis may be challenging due to the normal physiologic bowel herniation prior to 12 weeks of gestation (25, 26). However, a careful search of the fetal anatomy at the time of the nuchal translucency scan may reveal anatomic abnormalities consistent with the diagnosis. The sonographic appearances, either in the first or second trimester, provide the best diagnostic clues, though findings can vary significantly between cases. (26, 27) Cloacal exstrophy should be suspected in cases of two lower body abnormalities, most commonly a ventral wall defect and persistent non-visualization of the bladder. (28) Typically, the initial observation is omphalocele, which forms the cranial part of a complex abdominal wall defect extending to the pubis inferiorly. (28) Bowel herniation may be present between two bladder halves, forming an “elephant trunk.” The anal structures, which are easily visible after 22 weeks and routinely visible after 16 weeks (29), are frequently absent due to anal atresia. Ambiguous genitalia are often noted. Associated anomalies, including spinal and urinary tract anomalies are often present as well. (26-28)  3-dimensional ultrasound, fetal echocardiogram, and fetal MRI for further evaluation may be helpful to further evaluate the fetus and assist with further defining the fetal anatomy. (30, 31)

The differential diagnosis for lower abdominal wall defects includes bladder exstrophy (associated with a normal rectum and anus, and without omphalocele), and amniotic band syndrome (abdominoschisis). Body stalk anomalies can present with a large thoracoabdominal defect, but the fetus is typically adherent to the placenta and without an identifiable cord insertion. In isolated omphalocele the bladder is not included in the defect.

If a fetus is noted to have an absent bladder, the differntial diagnosis includes bladder exstrophy, renal anomalies resulting in anuria (e.g. bilateral renal agenesis, autosomal recessive polycystic kidney disease, bilatera multicystic dysplastic kidneys), placental insufficiency severe intrauterine growth restriction and oligohydramnios), and twin-twin transfusion syndrome.

The early suspicion for an abdominal wall defect, especially bellow the fetal abdominal cord insertion with an absent bladder should prompt an early fetal anatomy assessment and the diagnosis of OEIS should be considered.

The antenatal management of cloacal exstrophy includes diagnostic imaging and appropriate multidisciplinary counseling. Chorionic villuos sampling or amniocentesis for microarray/karyotyping, with cfDNA screening for patients who decline invasive testing should be considered. Patients should be counseled about the nature of the disorder, including need for complex and multiple surgeries, long-term complications and prognosis. (34) Termination should be offered after appropriate counseling. Should the patient choose to continue the pregnancy, serial growth assessment and reevaluation of the structural abnormalities should be performed. Arrangements should be made for delivery to occur at a tertiary care center. Although data is lacking about the optimal mode of delivery, most births occur via cesarean section.

After delivery, exposed organs and mucosal surfaces should be covered with sterile saline-soaked wrapping. Evaluation includes physical exam, baseline laboratory evaluation (including renal function testing, electrolyte evaluations, hematologic status and karyotyping if not previously performed), and baseline imaging (plain films, ultrasound or MRI as appropriate of the head, chest, abdominal, renal and spinal structure). Neonatal evaluation includes a multi-disciplinary approach with neonatology, general surgery, pediatric urology, neurosurgery, and orthopedic surgery. The initial surgical repair varies based on the constellation and severity of the defects. The goals of treatment include securing the abdominal wall, bladder closure, preservation of renal function, creation of functional and cosmetically acceptable genitalia, attainment of appropriate urinary and fecal continence. A retrospective study of 32 OEIS patients undergoing surgical repair concluded that the use of bioprosthetic material may be necessary in cases where it is not possible to achieve a tension-free abdominal wall through pelvic osteotomies and relaxing fascial incisions. (35) Older age at time of repair was associated with increased likelihood of needing bioprosthetic material to complete the repair. (35) Bowel and bladder control can be adversely affected by coesxisting CNS abnormalities, including myelomeningocele or tethered cord. In addition, serious consideration should be given to sex assignment, which may be difficult due to ambiguous genitalia. Sexual function in females may require vaginal reconstruction, and sexual function in males may be more difficult to accomplish. The provision of appropriate psychological support is important later in childhood.

The prognosis depends on the severity of the defects and associated anomalies. Of mothers whose fetuses are affected by cloacal exstrophy, 72% experience a live birth, 15.6% a stillbirth, and 12.9% choose pregnancy termination. (32) 51.1% of fetuses are delivered pre-term (18), often due to preterm labor secondary to polyhydramnios. Prior to the 1960s, mortality was 100%, but with surgical intervention, survival greater than 90% has been reported. (33) Complications include electrolyte abnormalities, failure to thrive, need for surgical interventions, long-term gastrointestinal and urinary dysfunction including incontinence, and psychological morbidity. In the event of coexisting spina bifida, movement issues may be present, the severity of which depends on the level of the lesion.

The risk of recurrence is extremely rare, though cases have been reported in siblings. (6, 8, 36-39)

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