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Spectrum of cloacal exstrophy
Seminars in Pediatric Surgery (2011) 20, 113-118
Spectrum of cloacal exstrophy Timothy M. Phillips, MD From the Department of Urology, Pediatric Urology, Wilford Hall Medical Center, Lackland AFB, Texas. KEYWORDS Cloacal exstrophy; OEIS; Bladder; Congenital
Cloacal exstrophy, one of the most severe congenital anomalies compatible with life, occurs in up to 1 in 200,000 lives births. The condition affects nearly every major organ system with severe neurologic, skeletal, gastrointestinal, and genitourinary ramifications. With increased understanding of the anatomy and embryology combined with refinements in prenatal diagnosis and postnatal care, there is now near-universal survival of patients with cloacal exstrophy. Functional and cosmetic outcomes have improved with modifications in surgical technique. However, debate continues regarding the issue of gender identity, and long-term data are still accruing with respect to the best strategy for management. Despite the extensive malformations noted, many patients have gone on to live fruitful lives. Published by Elsevier Inc. All rights reserved.
Cloacal exstrophy, commonly referred to as the omphalocele, exstrophy of the bladder, imperforate anus, and spinal abnormalities (OEIS) complex,1 represents one of the most severe congenital anomalies compatible with life and is thought to be related to abnormal development of the cloacal membrane. This results in an abdominal wall defect with failed closure of the lower urinary tract. Cloacal exstrophy comprises the most severe deformation along a spectrum which includes both epispadias and classic bladder exstrophy.2,3 Although first described in 1709 by Littre, historic survival rates were dismal secondary to sepsis or fluid, electrolyte, and nutritional deficits from short gut syndrome or intestinal obstruction.4 It was not until 1960 that the first long-term surviving case of cloacal exstrophy was reported.5 Since then, advances in neonatal care and surgical technique have resulted in present-day survival rates ranging from 83% to 100%.6-11 Modern management of cloacal exstrophy requires a multidisciplinary team-based approach, and the principle goals of treatment now focus upon optimization of
Address reprint requests and correspondence: Timothy M. Phillips, MD, Department of Urology, Pediatric Urology, 2200 Bergquist Dr, Ste1, Wilford Hall Medical Center, Lackland AFB, TX 78236. E-mail address: [email protected].
1055-8586/$ -see front matter Published by Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2010.12.007
patient function, psychosocial development, and overall quality of life.
Epidemiology/genetics The OEIS complex is seen in 1 of 200,000 to 400,000 live births,8 although the true incidence may be as high as 1 in 10,000 to 50,000 when one takes into account lack of diagnosis in stillborn infants.12 A 2:1 male preponderance has been observed,6,13 but more recent studies suggest no predilection towards either gender.14 A multivariate analysis of 29 cases in New York State revealed that the incidence of cloacal exstrophy appeared greatest in Hispanic mothers and least likely in black, non-Hispanic mothers.15 No single environmental exposure or consistent genetic defect has yet been identified, although both have been implicated as contributing factors.14,16,17 An unbalanced translocation between the long arms of chromosome 9 and the Y chromosome, resulting in a 9q34.1-qter deletion, has been cited as a potential cause, as have mutations in a group of homeobox genes, such as the HLXB9 and HOX family which are involved in the development of embryonic mesoderm.16,18,19 Reports of cloacal exstrophy among family members are generally anecdotal and have involved multi-
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generational relatives12,20 or non-twin siblings only in rare cases.21 However, multiple instances of affected monozygotic twins have been reported, which lends support to an underlying genetic link.22-26
Embryology Until the fifth week of gestation, the urinary, genital, and gastrointestinal tracts empty into a common chamber, the cloaca. At approximately the fourth week of development, lateral mesodermal tissue migrates medially between the endoderm and the overlying ectoderm thus forming the cloacal membrane. By the sixth week, this layer forms the infraumbilical abdominal wall. It is postulated that if mesodermal invasion does not occur, the infraumbilical cloacal membrane persists, with subsequent poor abdominal wall development, and is therefore prone to rupture.27 The urorectal septum begins to divide the cloaca into an anterior urogenital sinus and a posterior anorectal canal after the fourth week of gestation, and this septum descends caudally between weeks 6 and 8. If perforation of the anterior cloacal membrane occurs before complete descent of the urorectal septum, the common cloaca will be affected, and cloacal exstrophy will be the result. The various abnormalities observed in the exstrophyepispadias complex may be related to a common abnormal morphologic event: the migratory failure of the lateral mesodermal folds that prevented normal mesodermal ingrowth to the cloacal membrane.27 This lack of mesodermal reinforcement results in premature rupture of the membrane, the timing of which determines the extent of the abdominal wall defect and severity of urogenital tract involvement.2 Rupture of the cloacal membrane prior to fusion with the urorectal septum results in cloacal exstrophy, while late rupture some time after fusion gives rise to the less severe picture of bladder exstrophy. In the setting of cloacal exstrophy, it has been proposed that membrane rupture occurs sometime within the first 8 weeks of gestation.28 Although other contradictory developmental theories exist,29,30 rupture at 5 weeks, as previously postulated, would result in anterior herniation of the bladder and small bowel, which would prevent normal midline fusion of the hindgut, bladder plate, genital tubercles, and Müllerian ducts. The result is the traditional anatomic presentation of 2 exstrophied bladder halves separated by a strip of exstrophied cecum with associated prolapsed terminal ileum, hemi-phalli with a widely spaced pubic diastasis, an underdeveloped and blind-ending distal hindgut of varying length, and an associated omphalocele of varying size (Fig 1).
Gastrointestinal manifestations Gastrointestinal abnormalities can be a source of significant morbidity.31 Short bowel syndrome has been observed in up
Figure 1 Typical anatomic appearance of cloacal exstrophy: (O) Omphalocele; (BP) hemi-bladder templates; (IL) terminal ileum, prolapsed; (C) cecal plate; (UO) ureteral orifices; (CB) corporal bodies, widely separated; (HG) hindgut remnant. (Color version of figure is available online.)
to 25% of cases and may occur even in the presence of normal bowel length, implicating an inherent absorptive abnormality of the intestine.6,8,32 Ileocecal exstrophy with associated omphalocele, hindgut remnant and imperforate anus is the most common presentation.32 Omphaloceles are present in 88-100% and may contain portions of small bowel and/or liver.32,33 A recent review of 77 patients demonstrated that patients with 46 XX cloacal exstrophy had significantly longer hindgut segments than their 46 XY counterparts.34 Other findings include duplication anomalies, gastroschisis, ectopic perineal anus, exstrophied colonic segments, and malrotation.33,35 Immediate closure of the omphalocele defect in the newborn period is advised to prevent subsequent rupture.
Genitourinary manifestations Abnormalities of the upper urinary tract have been reported in 41%-66% of patients.8,33 Unilateral renal agenesis, pelvic kidney and/or hydronephrosis are observed in up to 33%.33 Less commonly reported are horseshoe kidneys, fusion anomalies, and ureteral abnormalities.8,32,33 Complete separation or even absence of the phallic or clitoral halves may be seen. The scrotum or labia are also widely divided. The testes are frequently undescended and associated with bilateral inguinal hernias. In females, failure of Mullerian duct fusion results in varying degrees of uterine duplication anomalies seen in up to 95% of patients.8,33 Vaginal duplication also occurs in 65% of patients, and vaginal agenesis can be found in approximately 25% to 50%.
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Spectrum of Cloacal Exstrophy
115
Central nervous system manifestations
Prenatal diagnosis
Some form of spinal dysraphism, including tethered cord, myelomeningocele, or lipomyelomeningocele, is present in nearly all patients, with recent reports ranging from 64% to 100%.10,12,35,36 Given the high incidence of spinal cord or vertebral anomalies in affected patients, the use of magnetic resonance imaging (MRI) as a routine part of the newborn evaluation in cloacal exstrophy is recommended.28 Neurologic impairment is variable and may affect bladder function, urinary continence, lower extremity movement and erectile function. The challenge of achieving continence in this patient population is likely related to the frequency of coexisting myelodysplasia.28,36,37 In addition, detailed postmortem microdissection of the pelvis of an infant with cloacal exstrophy revealed both aberrant origin and vascular supply of the autonomic nerves.38 The innervation of the hemibladders and corporal bodies arises from a pelvic plexus on the anterior surface of the rectum. The nerves to the hemibladders travel the midline along the posterior inferior surface of the rectum and extend laterally to the hemibladders. Innervation to the duplicated corporal bodies arises from the sacral complex, travels in the midline, perforates the inferior portion of the pelvic floor, and courses medially to the hemibladders. These nerves may be at additional risk of iatrogenic injury during dissection and separation of the cecal plate from the bladder halves.
The use of ultrasound in prenatal evaluation has made the early diagnosis of the OIES complex possible, thus allowing for parental counseling and education. Should cloacal exstrophy be suspected on prenatal imaging, referral should be made to a tertiary care center for further evaluation. Prenatal diagnosis by ultrasound was first reported in 1985.43 Since then, several authors have proposed criteria for the prenatal diagnosis of cloacal exstrophy, and principle findings include failure to visualize the urinary bladder, a large midline infraumbilical anterior abdominal wall defect, and/or lumbosacral myelomeningocele.25,43-46 The prolapsed ileal segment unique to cloacal exstrophy, may be visualized as an “elephant trunk-like” mass on prenatal ultrasound, and has also been reported as a pathognomonic finding.47 On the basis of the frequency with which certain abnormalities were observed, a refined list of diagnostic findings has been developed by characterizing certain features as either major or minor criteria for prenatal ultrasound diagnosis of cloacal exstrophy. Major criteria were those seen in ⬎50% of cases and included: nonvisualization of the bladder (91%), a large midline infraumbilical anterior wall defect or cystic anterior wall structure (82%), omphalocele (77%), and myelomeningocele (68%). Minor criteria, seen in ⬍50%, consisted of lower extremity defects (23%), renal anomalies (23%), ascites (41%), widened pubic arches (18%), narrow thorax (9%), hydrocephalus (9%), and single umbilical artery (9%).44 Despite the application of these refined criteria, a recent report of 15 new cases argues that, despite prenatal ultrasound, accurate prenatal diagnosis of cloacal exstrophy may still be confounded by confusion with isolated omphalocele, classic bladder exstrophy or other midline abdominal wall defects.18 In this series, only slightly more than onehalf of patients were prenatally diagnosed with cloacal exstrophy on the basis of ultrasound findings, leading the authors to caution that the full extent of abnormalities may not be clear until postnatal examination.18 More recently, prenatal diagnosis with MRI has been reported and may hold promise for the future.48
Skeletal manifestations The skeletal system may be affected at multiple levels, with involvement of the vertebral column, pelvis, and limbs. Spinal abnormalities, excluding myelodysplasia, have been reported in the range of 22%-60% consisting mainly of absent or extra vertebrae, scoliosis and kyphosis.32,39,40 Pelvic deformity is characterized by a widened pubic diastasis with external angling of the posterior and anterior segments.41 The iliac wings are externally rotated and abducted. These pelvic deformities are also seen in the setting of classic bladder exstrophy but are considerably more pronounced in cloacal cases. Pubic diastasis is often twice that seen in classic bladder exstrophy, and a higher tendency towards side-to-side asymmetry is also observed.41 The incidence of lower limb abnormalities in patients with cloacal exstrophy is reported to be 17%-26%.42 Certain limb malformations like club foot and equinovarus deformities can be associated with myelomeningocele, which often accompanies cloacal exstrophy. However, a variety of true limb malformations, including hypoplasia, absence, split foot and ectopic additional digits, have also been observed.42 Given the mesodermal origin of internal limb structures, it is postulated that mesodermal deficiency in the caudal region of the developing embryo is the common underlying abnormality.42
Postnatal management Immediately after birth and stabilization of the newborn, exposed organs/mucosal surfaces, including the omphalocele, bladder, intestine, and myelomeningocele, should be protected by enclosing the infant’s lower torso in a bowel bag or by first moistening surfaces with saline and covering with sterile plastic wrapping.49 These measures aid in prevention of evaporative losses, trauma and infection.49,50 The urological examination should attempt to note genetic sex, size of hemi-bladders, and presence of spinal dysraphism. Baseline renal function, electrolyte and hematologic status should be determined through routine serologic testing. Karyotyping can be performed if gender has not been pre-
116 viously determined or is not obvious on examination. Initial imaging should include plain films of the chest and spine along with head, chest, abdominal, renal, and spinal ultrasounds. If not obvious on examination or ultrasound, MRI of the spine may be advisable for detection of occult lesions, such as tethered cord. In addition to the urological evaluation, consultation should be made to general surgery, neurosurgery and orthopedics for operative planning. Once initial evaluation is complete, discussion should be had with the parents regarding gender assignment, surgical reconstruction, possible functional deficits, and overall expected quality of life.49
Gender assignment and identity Gender assignment continues to be a difficult and significant issue in the management of patients with cloacal exstrophy. The phallic halves are typically diminutive, asymmetric, and widely separated making reconstruction challenging, if not impossible. Historically, a genetically male infant with a phallus felt inadequate for reconstruction was routinely assigned to female gender, undergoing early orchiectomy with subsequent hormone replacement at puberty.51 The appropriateness of this decision has now been evaluated by several authors, leading to increased awareness but also additional controversy in the gender reassignment of these patients. It is important to remember that cloacal exstrophy is not a disorder of sexual differentiation and that genetically male patients have histologically normal testicles with normal response to antenatal androgens in utero, as would be expected. A recent survey of 185 active members in the Section of Urology of the American Academy of Pediatrics revealed that although most surgeons had limited experience with this rare disorder, 70% agreed that male assignment was the most appropriate choice in the management of 46XY cloacal exstrophy, with the most important factor in decision-making being androgenic influence on the developing brain. Clinicians with more than 15 years experience were twice as likely to recommend gender reassignment, likely reflecting the historical preference.52 Although current views appear to support maintaining male gender in those patients with 46XY, the severe phallic inadequacy that may exist continues to complicate the “best” reconstructive option for these infants. Recent use of radial forearm freeflap techniques for penile reconstruction proves promising for the young adult male with cloacal exstrophy and severe phallic insufficiency.53 A more detailed review of the issues regarding gender assignment is provided elsewhere in this symposium.
Principles of initial repair Surgical management of cloacal exstrophy is typically undertaken in the newborn period (48-72 hours) as a combined
Seminars in Pediatric Surgery, Vol 20, No 2, May 2011 effort between pediatric surgery and urology. In the setting of associated spinal dysraphism, neurosurgical consultation and closure should be undertaken as soon as the infant is medically stable. It is generally agreed that an individualized approach towards reconstruction of the genitourinary and gastrointestinal tract, whether in a single or multistaged procedure, results in the best long-term outcomes.54 The goals of treatment encompass secure abdominal wall and bladder closure, preservation of renal function, prevention of short bowel syndrome, creation of functional and cosmetically acceptable genitalia, and attainment of acceptable urinary and fecal continence.9,36 Although various algorithms have been published, all approaches emphasize initial separation of the intervening cecal plate from the 2 bladder halves, omphalocele closure, and hindgut preservation.6-9,11,54 Although a detailed review of the bowel management in cloacal exstrophy is offered elsewhere in this symposium, the omphalocele is typically excised to facilitate abdominal wall closure. Closure may be complicated by development of abdominal compartment syndrome, and in cases of large omphaloceles a complete initial reduction may not possible. In this setting, a silo device may be used. Alternatively, the omphalocele may be allowed to reepithelialize, thus converting it to a ventral hernia which may be repaired at a later time.36 The hemi-bladders are then dissected free and approximated in the posterior midline. In infants with few other associated malformations, who are medically stable, complete closure of the abdominal wall, bladder, and phallic halves may be undertaken at this point in a single-stage procedure with or without osteotomy. However, the preferred option at our institution is initial approximation of the bladder halves at birth followed by staged osteotomy and bladder closure at 1-2 years of life. In a recent review, researchers compared a series of patients undergoing primary versus delayed bladder closure. They concluded that while single-staged repair might be applicable to a very select subset of patients, small bladder plates, wide diastases or large omphaloceles often precluded primary closure, and thus make delayed closure after gastrointestinal diversion more appropriate. Furthermore, with the high incidence of associated spinal dysraphism, most patients required multiple later surgical procedures to achieve adequate bladder capacity and continence.37
Sexual function Vaginal reconstruction is generally undertaken early in the female patient, as the vagina must be separated from the urinary tract at the time of initial closure.10,32 The native vagina, although often foreshortened, may be adequate to reconstruct at the perineum. Alternatively, creation of a neovagina later in life may be performed through use of large or small bowel.10,55 A review of 5 adult women with cloacal exstrophy demonstrated that 3 were sexually active. Two of the sexually active subjects reported good overall
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Spectrum of Cloacal Exstrophy
sexual satisfaction, despite the presence of a urinary stoma in both. The 2 women who were not sexually active reported reluctance because of genital appearance and presence of a stoma, respectively. One patient had a successful pregnancy and delivered by Cesarean, although this was complicated by perforation of her continent diversion, postpartum uterine prolapse, and development of incontinence from her urinary stoma. In fact, vaginal prolapse was reported in 2 of 5 adult patients and appears to be a frequent problem among females with the exstrophy-epispadias complex.56 There remains a paucity of literature on male sexual function. A review of 8 genotypic male patients who did not undergo gender reassignment and underwent phallic reconstruction demonstrated that all had phallic inadequacy with belowaverage penile length. Sexual histories revealed feelings of sexual inadequacy in all the postpubertal patients. Half of these individuals demonstrated absence of erectile function on nocturnal penile tumescence testing. In the other 2 patients with intact erectile function, one reported difficulty with vaginal penetration secondary to inadequate penile length, while the other was married and able to engage in successful vaginal intercourse.57 Although it is difficult to make definitive recommendations or conclusions based on these small studies, it is clear that considerations of sexual function outcomes must be included in the management of cloacal exstrophy.
Conclusions Cloacal exstrophy remains a rare and challenging diagnosis. Advances in medical and surgical management have allowed for dramatically improved survival and continence rates. However, the chronic nature of cloacal exstrophy must be emphasized. Afflicted patients generally require multiple surgical procedures and will clearly face medical, psychological and social challenges throughout their lives. It is therefore important that these individuals and their families remain under the care of a multidisciplinary team of providers who can offer medical care, counseling and lifelong follow up.
References 1. Carey JC, Greenbaum B, Hall BD. The OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects). Birth Defects 1978;15: 253-63. 2. Muecke EC. The role of the cloacal membrane in exstrophy: The first successful experimental study. J Urol 1964;92:659-67. 3. Ambrose SS, O’Brien DP 3rd. Surgical embryology of the exstrophyepispadias complex. Surg Clin North Am 1974;54:1379-90. 4. Med-Littre A. Acad R Sci 1709;4:9. 5. Rickham PP. Vesico-intestinal fissure. Arch Dis Child 1960;35:97102. 6. Diamond DA, Jeffs RD. Cloacal exstrophy: A 22-year experience. J Urol 1985;133:779-82.
117 7. Howell C, Caldamone A, Snyder H, et al. Optimal management of cloacal exstrophy. J Pediatr Surg 1983;18:365-9. 8. Hurwitz RS, Manzoni GA, Ransley PG, et al. Cloacal exstrophy: A report of 34 cases. J Urol 1987;138:1060-4. 9. Ricketts RR, Woodard JR, Zwiren GT, et al. Modern treatment of cloacal exstrophy. J Pediatr Surg 1991;26:448-50. 10. Lund DP, Hendren WH. Cloacal exstrophy: A 25-year experience with 50 cases. J Pediatr Surg 2001;36:68-75. 11. Mitchell ME, Plaire C. Management of cloacal exstrophy. Adv Exp Med Biol 2002;511:270-3. 12. Keppler-Noreuil KM. OEIS Complex (omphalocele-exstrophy-imperforate anus-spinal defects): A review of 14 cases. Am J Med Genet 2001;99:271-9. 13. Gearhart JP, Mathews R. Exstrophy-epispadias complex. In: Wein AJ, et al., eds Campbell-Walsh Urology. Philadelphia, PA: W. B. Saunders, 2007:3538-44. 14. Boyadjiev SA, Dodson JL, Radford CL, et al. Clinical and molecular characterization of the bladder exstrophy-epispadias complex: Analysis of 232 families. BJU Int 2004;94:1337-43. 15. Caton AR, Bloom A, Druschel CM, et al. Epidemiology of bladder and cloacal exstrophies in New York State, 1983-1999. Birth Defects Res A Clin Mol Teratol 2007;79:781-7. 16. Thauvin-Robinet C, Faivre L, Cusin V, et al. Cloacal exstrophy in an infant with 9q34.1-qter deletion resulting from a de novo unbalanced translocation between chromosome 9q and Yq. Am J Med Genet A 2004;126A:303-7. 17. Manner J, Kluth D. The morphogenesis of the exstrophy-epispadias complex: A new concept based on observations made in early embryonic cases of cloacal exstrophy. Anat Embryol (Berl) 2005;210:51-7. 18. Keppler-Noreuil K, Gorton S, Foo F, et al. Prenatal ascertainment of OEIS complex/cloacal exstrophy—15 new cases and literature review. Am J Med Genet A 2007;143A:2122-8. 19. Evans JA, Chudley AE. Tibial agenesis, femoral duplication, and caudal midline anomalies. Am J Med Genet 1999;85:13-9. 20. Gambhir L, Höller T, Müller M, et al. Epidemiological survey of 214 families with bladder exstrophy-epispadias complex. J Urol 2008;179: 1539-43. 21. Smith NM, Chambers HM, Furness ME, et al. The OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects): Recurrence in sibs. J Med Genet 1992;29:730-2. 22. Koffler H, Aase JM, Papile LA, et al. Persistent cloaca with absent penis and anal atresia in one of identical twins. J Pediatr 1978;93: 821-3. 23. Redman JF, Seibert JJ, Page BC. Cloacal exstrophy in identical twins. Urology 1981;17:73-4. 24. McLaughlin JF, Marks WM, Jones G. Prospective management of exstrophy of the cloaca and myelocystocele following prenatal ultrasound recognition of neural tube defects in identical twins. Am J Med Genet 1984;19:721-7. 25. Chitrit Y, Zorn B, Filidori M, et al. Cloacal exstrophy in monozygotic twins detected through antenatal ultrasound scanning. J Clin Ultrasound 1993;21:339-42. 26. Lee DH, Cottrell JR, Sanders RC, et al. OEIS complex (omphaloceleexstrophy-imperforate anus-spinal defects) in monozygotic twins. Am J Med Genet 1999;84:29-33. 27. Purves JT, Gearhart JP. The bladder exstrophy-epispadias-cloacal exstrophy complex. In: Gearhart JP, Rink RC, Mouriquand P, eds. Pediatric Urology Philadelphia, PA: W. B. Saunders, 2010:410-5. 28. McLaughlin KP, Rink RC, Kalsbeck JE, et al. Cloacal exstrophy: The neurological implications. J Urol 1995;154:782-4. 29. Langer JC, Brennan B, Lappalainen RE, et al. Cloacal exstrophy: Prenatal diagnosis before rupture of the cloacal membrane. J Pediatr Surg 1992;27:1352-5. 30. Bruch SW, Adzick NS, Goldstein RB, et al. Challenging the embryogenesis of cloacal exstrophy. J Pediatr Surg 1996;31:768-70. 31. Davidoff AM, Hebra A, Balmer D, et al. Management of the gastrointestinal tract and nutrition in patients with cloacal exstrophy. J Pediatr Surg 1996;31:771-3.
118 32. Mathews R, Jeffs RD, Reiner WG, et al. Cloacal exstrophy–improving the quality of life: the Johns Hopkins experience. J Urol 1998;160: 2452-6. 33. Diamond DA. Management of cloacal exstrophy. Dial. J Pediatr Urol 1990;13:2. 34. Sawaya D, Goldstein S, Seetharamaiah R, et al. Gastrointestinal ramifications of the cloacal exstrophy complex: A 44-year experience. J Pediatr Surg 2010;45:171-5. 35. McHoney M, Ransley PG, Duffy P, et al. Cloacal exstrophy: Morbidity associated with abnormalities of the gastrointestinal tract and spine. J Pediatr Surg 2004;39:1209-13. 36. Gearhart JP, Jeffs RD. Techniques to create urinary continence in the cloacal exstrophy patient. J Urol 1991;146:616-8. 37. Thomas JC, DeMarco RT, Pope JC 4th, et al. First stage approximation of the exstrophic bladder in patients with cloacal exstrophy—Should this be the initial surgical approach in all patients? J Urol 2007;178: 1635-6. 38. Schlegel PN, Gearhart JP. Neuroanatomy of the pelvis in an infant with cloacal exstrophy: A detailed microdissection with histology. J Urol 1989;141:583-5. 39. Loder RT, Dayioglu MM. Association of congenital vertebral malformations with bladder and cloacal exstrophy. J Pediatr Orthop 1990; 10:389-93. 40. Greene WB, Dias LS, Lindseth RE, et al. Musculoskeletal problems in association with cloacal exstrophy. J Bone Joint Surg Am 1991;73: 551-60. 41. Sponseller PD, Bisson LJ, Gearhart JP, et al. The anatomy of the pelvis in the exstrophy complex. J Bone Joint Surg Am 1995;77:177-89. 42. Jain M, Weaver DD. Severe lower limb defects in exstrophy of the cloaca. Am J Med Genet A 2004;128A:320-4. 43. Meizner I, Bar-Ziv J. Prenatal ultrasonic diagnosis of cloacal exstrophy. Am J Obstet Gynecol 1985;153:802-3. 44. Austin PF, Homsy YL, Gearhart JP, et al. The prenatal diagnosis of cloacal exstrophy. J Urol 1998;160:1179-81.
Seminars in Pediatric Surgery, Vol 20, No 2, May 2011 45. Richards DS, Langham MR Jr, Mahaffey SM. The prenatal ultrasonographic diagnosis of cloacal exstrophy. J Ultrasound Med 1992;11: 507-10. 46. Meizner I, Levy A, Barnhard Y. Cloacal exstrophy sequence: An exceptional ultrasound diagnosis. Obstet Gynecol 1995;86:446-50. 47. Hamada H, Takano K, Shiina H, et al. New ultrasonographic criterion for the prenatal diagnosis of cloacal exstrophy: Elephant trunk-like image. J Urol 1999;162:2123-4. 48. Gobbi D, Fascetti-Leon F, Tregnaghi A, et al. Early prenatal diagnosis of cloacal exstrophy with fetal magnetic resonance imaging. Fetal Diagn Ther 2008;24:437-9. 49. Woo LL, Thomas JC, Brock JW. Cloacal exstrophy: A comprehensive review of an uncommon problem. J Pediatr Urol 2010;6:102-11. 50. Lund DP, Hendren WH. Cloacal exstrophy: Experience with 20 cases. J Pediatr Surg 1993;28:1368-9. 51. Tank ES, Lindenauer SM. Principles of management of exstrophy of the cloaca. Am J Surg 1970;119:95-8. 52. Diamond DA, Burns JP, Mitchell C, et al. Sex assignment for newborns with ambiguous genitalia and exposure to fetal testosterone: Attitudes and practices of pediatric urologists. J Pediatr 2006;148: 445-9. 53. Timsit MO, Mouriquand PE, Ruffion A, et al. Use of forearm free-flap phalloplasty in bladder exstrophy adults. BJU Int 2009;103:1418-21. 54. Stolar CH, Randolph JG, Flanigan LP. Cloacal exstrophy: Individualized management through a staged surgical approach. J Pediatr Surg 1990;25:505-7. 55. Soffer SZ, Rosen NG, Hong AR, et al. Cloacal exstrophy: A unified management plan. J Pediatr Surg 2000;35:932-7. 56. Mathews RI, Gan M, Gearhart JP. Urogynaecological and obstetric issues in women with the exstrophy-epispadias complex. BJU Int 2003;9:845-9. 57. Husmann DA, McLorie GA, Churchill BM. Phallic reconstruction in cloacal exstrophy. J Urol 1989;142:563-4.
Spectrum of cloacal exstrophy Timothy M. Phillips, MD From the Department of Urology, Pediatric Urology, Wilford Hall Medical Center, Lackland AFB, Texas. KEYWORDS Cloacal exstrophy; OEIS; Bladder; Congenital
Cloacal exstrophy, one of the most severe congenital anomalies compatible with life, occurs in up to 1 in 200,000 lives births. The condition affects nearly every major organ system with severe neurologic, skeletal, gastrointestinal, and genitourinary ramifications. With increased understanding of the anatomy and embryology combined with refinements in prenatal diagnosis and postnatal care, there is now near-universal survival of patients with cloacal exstrophy. Functional and cosmetic outcomes have improved with modifications in surgical technique. However, debate continues regarding the issue of gender identity, and long-term data are still accruing with respect to the best strategy for management. Despite the extensive malformations noted, many patients have gone on to live fruitful lives. Published by Elsevier Inc. All rights reserved.
Cloacal exstrophy, commonly referred to as the omphalocele, exstrophy of the bladder, imperforate anus, and spinal abnormalities (OEIS) complex,1 represents one of the most severe congenital anomalies compatible with life and is thought to be related to abnormal development of the cloacal membrane. This results in an abdominal wall defect with failed closure of the lower urinary tract. Cloacal exstrophy comprises the most severe deformation along a spectrum which includes both epispadias and classic bladder exstrophy.2,3 Although first described in 1709 by Littre, historic survival rates were dismal secondary to sepsis or fluid, electrolyte, and nutritional deficits from short gut syndrome or intestinal obstruction.4 It was not until 1960 that the first long-term surviving case of cloacal exstrophy was reported.5 Since then, advances in neonatal care and surgical technique have resulted in present-day survival rates ranging from 83% to 100%.6-11 Modern management of cloacal exstrophy requires a multidisciplinary team-based approach, and the principle goals of treatment now focus upon optimization of
Address reprint requests and correspondence: Timothy M. Phillips, MD, Department of Urology, Pediatric Urology, 2200 Bergquist Dr, Ste1, Wilford Hall Medical Center, Lackland AFB, TX 78236. E-mail address: [email protected].
1055-8586/$ -see front matter Published by Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2010.12.007
patient function, psychosocial development, and overall quality of life.
Epidemiology/genetics The OEIS complex is seen in 1 of 200,000 to 400,000 live births,8 although the true incidence may be as high as 1 in 10,000 to 50,000 when one takes into account lack of diagnosis in stillborn infants.12 A 2:1 male preponderance has been observed,6,13 but more recent studies suggest no predilection towards either gender.14 A multivariate analysis of 29 cases in New York State revealed that the incidence of cloacal exstrophy appeared greatest in Hispanic mothers and least likely in black, non-Hispanic mothers.15 No single environmental exposure or consistent genetic defect has yet been identified, although both have been implicated as contributing factors.14,16,17 An unbalanced translocation between the long arms of chromosome 9 and the Y chromosome, resulting in a 9q34.1-qter deletion, has been cited as a potential cause, as have mutations in a group of homeobox genes, such as the HLXB9 and HOX family which are involved in the development of embryonic mesoderm.16,18,19 Reports of cloacal exstrophy among family members are generally anecdotal and have involved multi-
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generational relatives12,20 or non-twin siblings only in rare cases.21 However, multiple instances of affected monozygotic twins have been reported, which lends support to an underlying genetic link.22-26
Embryology Until the fifth week of gestation, the urinary, genital, and gastrointestinal tracts empty into a common chamber, the cloaca. At approximately the fourth week of development, lateral mesodermal tissue migrates medially between the endoderm and the overlying ectoderm thus forming the cloacal membrane. By the sixth week, this layer forms the infraumbilical abdominal wall. It is postulated that if mesodermal invasion does not occur, the infraumbilical cloacal membrane persists, with subsequent poor abdominal wall development, and is therefore prone to rupture.27 The urorectal septum begins to divide the cloaca into an anterior urogenital sinus and a posterior anorectal canal after the fourth week of gestation, and this septum descends caudally between weeks 6 and 8. If perforation of the anterior cloacal membrane occurs before complete descent of the urorectal septum, the common cloaca will be affected, and cloacal exstrophy will be the result. The various abnormalities observed in the exstrophyepispadias complex may be related to a common abnormal morphologic event: the migratory failure of the lateral mesodermal folds that prevented normal mesodermal ingrowth to the cloacal membrane.27 This lack of mesodermal reinforcement results in premature rupture of the membrane, the timing of which determines the extent of the abdominal wall defect and severity of urogenital tract involvement.2 Rupture of the cloacal membrane prior to fusion with the urorectal septum results in cloacal exstrophy, while late rupture some time after fusion gives rise to the less severe picture of bladder exstrophy. In the setting of cloacal exstrophy, it has been proposed that membrane rupture occurs sometime within the first 8 weeks of gestation.28 Although other contradictory developmental theories exist,29,30 rupture at 5 weeks, as previously postulated, would result in anterior herniation of the bladder and small bowel, which would prevent normal midline fusion of the hindgut, bladder plate, genital tubercles, and Müllerian ducts. The result is the traditional anatomic presentation of 2 exstrophied bladder halves separated by a strip of exstrophied cecum with associated prolapsed terminal ileum, hemi-phalli with a widely spaced pubic diastasis, an underdeveloped and blind-ending distal hindgut of varying length, and an associated omphalocele of varying size (Fig 1).
Gastrointestinal manifestations Gastrointestinal abnormalities can be a source of significant morbidity.31 Short bowel syndrome has been observed in up
Figure 1 Typical anatomic appearance of cloacal exstrophy: (O) Omphalocele; (BP) hemi-bladder templates; (IL) terminal ileum, prolapsed; (C) cecal plate; (UO) ureteral orifices; (CB) corporal bodies, widely separated; (HG) hindgut remnant. (Color version of figure is available online.)
to 25% of cases and may occur even in the presence of normal bowel length, implicating an inherent absorptive abnormality of the intestine.6,8,32 Ileocecal exstrophy with associated omphalocele, hindgut remnant and imperforate anus is the most common presentation.32 Omphaloceles are present in 88-100% and may contain portions of small bowel and/or liver.32,33 A recent review of 77 patients demonstrated that patients with 46 XX cloacal exstrophy had significantly longer hindgut segments than their 46 XY counterparts.34 Other findings include duplication anomalies, gastroschisis, ectopic perineal anus, exstrophied colonic segments, and malrotation.33,35 Immediate closure of the omphalocele defect in the newborn period is advised to prevent subsequent rupture.
Genitourinary manifestations Abnormalities of the upper urinary tract have been reported in 41%-66% of patients.8,33 Unilateral renal agenesis, pelvic kidney and/or hydronephrosis are observed in up to 33%.33 Less commonly reported are horseshoe kidneys, fusion anomalies, and ureteral abnormalities.8,32,33 Complete separation or even absence of the phallic or clitoral halves may be seen. The scrotum or labia are also widely divided. The testes are frequently undescended and associated with bilateral inguinal hernias. In females, failure of Mullerian duct fusion results in varying degrees of uterine duplication anomalies seen in up to 95% of patients.8,33 Vaginal duplication also occurs in 65% of patients, and vaginal agenesis can be found in approximately 25% to 50%.
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Central nervous system manifestations
Prenatal diagnosis
Some form of spinal dysraphism, including tethered cord, myelomeningocele, or lipomyelomeningocele, is present in nearly all patients, with recent reports ranging from 64% to 100%.10,12,35,36 Given the high incidence of spinal cord or vertebral anomalies in affected patients, the use of magnetic resonance imaging (MRI) as a routine part of the newborn evaluation in cloacal exstrophy is recommended.28 Neurologic impairment is variable and may affect bladder function, urinary continence, lower extremity movement and erectile function. The challenge of achieving continence in this patient population is likely related to the frequency of coexisting myelodysplasia.28,36,37 In addition, detailed postmortem microdissection of the pelvis of an infant with cloacal exstrophy revealed both aberrant origin and vascular supply of the autonomic nerves.38 The innervation of the hemibladders and corporal bodies arises from a pelvic plexus on the anterior surface of the rectum. The nerves to the hemibladders travel the midline along the posterior inferior surface of the rectum and extend laterally to the hemibladders. Innervation to the duplicated corporal bodies arises from the sacral complex, travels in the midline, perforates the inferior portion of the pelvic floor, and courses medially to the hemibladders. These nerves may be at additional risk of iatrogenic injury during dissection and separation of the cecal plate from the bladder halves.
The use of ultrasound in prenatal evaluation has made the early diagnosis of the OIES complex possible, thus allowing for parental counseling and education. Should cloacal exstrophy be suspected on prenatal imaging, referral should be made to a tertiary care center for further evaluation. Prenatal diagnosis by ultrasound was first reported in 1985.43 Since then, several authors have proposed criteria for the prenatal diagnosis of cloacal exstrophy, and principle findings include failure to visualize the urinary bladder, a large midline infraumbilical anterior abdominal wall defect, and/or lumbosacral myelomeningocele.25,43-46 The prolapsed ileal segment unique to cloacal exstrophy, may be visualized as an “elephant trunk-like” mass on prenatal ultrasound, and has also been reported as a pathognomonic finding.47 On the basis of the frequency with which certain abnormalities were observed, a refined list of diagnostic findings has been developed by characterizing certain features as either major or minor criteria for prenatal ultrasound diagnosis of cloacal exstrophy. Major criteria were those seen in ⬎50% of cases and included: nonvisualization of the bladder (91%), a large midline infraumbilical anterior wall defect or cystic anterior wall structure (82%), omphalocele (77%), and myelomeningocele (68%). Minor criteria, seen in ⬍50%, consisted of lower extremity defects (23%), renal anomalies (23%), ascites (41%), widened pubic arches (18%), narrow thorax (9%), hydrocephalus (9%), and single umbilical artery (9%).44 Despite the application of these refined criteria, a recent report of 15 new cases argues that, despite prenatal ultrasound, accurate prenatal diagnosis of cloacal exstrophy may still be confounded by confusion with isolated omphalocele, classic bladder exstrophy or other midline abdominal wall defects.18 In this series, only slightly more than onehalf of patients were prenatally diagnosed with cloacal exstrophy on the basis of ultrasound findings, leading the authors to caution that the full extent of abnormalities may not be clear until postnatal examination.18 More recently, prenatal diagnosis with MRI has been reported and may hold promise for the future.48
Skeletal manifestations The skeletal system may be affected at multiple levels, with involvement of the vertebral column, pelvis, and limbs. Spinal abnormalities, excluding myelodysplasia, have been reported in the range of 22%-60% consisting mainly of absent or extra vertebrae, scoliosis and kyphosis.32,39,40 Pelvic deformity is characterized by a widened pubic diastasis with external angling of the posterior and anterior segments.41 The iliac wings are externally rotated and abducted. These pelvic deformities are also seen in the setting of classic bladder exstrophy but are considerably more pronounced in cloacal cases. Pubic diastasis is often twice that seen in classic bladder exstrophy, and a higher tendency towards side-to-side asymmetry is also observed.41 The incidence of lower limb abnormalities in patients with cloacal exstrophy is reported to be 17%-26%.42 Certain limb malformations like club foot and equinovarus deformities can be associated with myelomeningocele, which often accompanies cloacal exstrophy. However, a variety of true limb malformations, including hypoplasia, absence, split foot and ectopic additional digits, have also been observed.42 Given the mesodermal origin of internal limb structures, it is postulated that mesodermal deficiency in the caudal region of the developing embryo is the common underlying abnormality.42
Postnatal management Immediately after birth and stabilization of the newborn, exposed organs/mucosal surfaces, including the omphalocele, bladder, intestine, and myelomeningocele, should be protected by enclosing the infant’s lower torso in a bowel bag or by first moistening surfaces with saline and covering with sterile plastic wrapping.49 These measures aid in prevention of evaporative losses, trauma and infection.49,50 The urological examination should attempt to note genetic sex, size of hemi-bladders, and presence of spinal dysraphism. Baseline renal function, electrolyte and hematologic status should be determined through routine serologic testing. Karyotyping can be performed if gender has not been pre-
116 viously determined or is not obvious on examination. Initial imaging should include plain films of the chest and spine along with head, chest, abdominal, renal, and spinal ultrasounds. If not obvious on examination or ultrasound, MRI of the spine may be advisable for detection of occult lesions, such as tethered cord. In addition to the urological evaluation, consultation should be made to general surgery, neurosurgery and orthopedics for operative planning. Once initial evaluation is complete, discussion should be had with the parents regarding gender assignment, surgical reconstruction, possible functional deficits, and overall expected quality of life.49
Gender assignment and identity Gender assignment continues to be a difficult and significant issue in the management of patients with cloacal exstrophy. The phallic halves are typically diminutive, asymmetric, and widely separated making reconstruction challenging, if not impossible. Historically, a genetically male infant with a phallus felt inadequate for reconstruction was routinely assigned to female gender, undergoing early orchiectomy with subsequent hormone replacement at puberty.51 The appropriateness of this decision has now been evaluated by several authors, leading to increased awareness but also additional controversy in the gender reassignment of these patients. It is important to remember that cloacal exstrophy is not a disorder of sexual differentiation and that genetically male patients have histologically normal testicles with normal response to antenatal androgens in utero, as would be expected. A recent survey of 185 active members in the Section of Urology of the American Academy of Pediatrics revealed that although most surgeons had limited experience with this rare disorder, 70% agreed that male assignment was the most appropriate choice in the management of 46XY cloacal exstrophy, with the most important factor in decision-making being androgenic influence on the developing brain. Clinicians with more than 15 years experience were twice as likely to recommend gender reassignment, likely reflecting the historical preference.52 Although current views appear to support maintaining male gender in those patients with 46XY, the severe phallic inadequacy that may exist continues to complicate the “best” reconstructive option for these infants. Recent use of radial forearm freeflap techniques for penile reconstruction proves promising for the young adult male with cloacal exstrophy and severe phallic insufficiency.53 A more detailed review of the issues regarding gender assignment is provided elsewhere in this symposium.
Principles of initial repair Surgical management of cloacal exstrophy is typically undertaken in the newborn period (48-72 hours) as a combined
Seminars in Pediatric Surgery, Vol 20, No 2, May 2011 effort between pediatric surgery and urology. In the setting of associated spinal dysraphism, neurosurgical consultation and closure should be undertaken as soon as the infant is medically stable. It is generally agreed that an individualized approach towards reconstruction of the genitourinary and gastrointestinal tract, whether in a single or multistaged procedure, results in the best long-term outcomes.54 The goals of treatment encompass secure abdominal wall and bladder closure, preservation of renal function, prevention of short bowel syndrome, creation of functional and cosmetically acceptable genitalia, and attainment of acceptable urinary and fecal continence.9,36 Although various algorithms have been published, all approaches emphasize initial separation of the intervening cecal plate from the 2 bladder halves, omphalocele closure, and hindgut preservation.6-9,11,54 Although a detailed review of the bowel management in cloacal exstrophy is offered elsewhere in this symposium, the omphalocele is typically excised to facilitate abdominal wall closure. Closure may be complicated by development of abdominal compartment syndrome, and in cases of large omphaloceles a complete initial reduction may not possible. In this setting, a silo device may be used. Alternatively, the omphalocele may be allowed to reepithelialize, thus converting it to a ventral hernia which may be repaired at a later time.36 The hemi-bladders are then dissected free and approximated in the posterior midline. In infants with few other associated malformations, who are medically stable, complete closure of the abdominal wall, bladder, and phallic halves may be undertaken at this point in a single-stage procedure with or without osteotomy. However, the preferred option at our institution is initial approximation of the bladder halves at birth followed by staged osteotomy and bladder closure at 1-2 years of life. In a recent review, researchers compared a series of patients undergoing primary versus delayed bladder closure. They concluded that while single-staged repair might be applicable to a very select subset of patients, small bladder plates, wide diastases or large omphaloceles often precluded primary closure, and thus make delayed closure after gastrointestinal diversion more appropriate. Furthermore, with the high incidence of associated spinal dysraphism, most patients required multiple later surgical procedures to achieve adequate bladder capacity and continence.37
Sexual function Vaginal reconstruction is generally undertaken early in the female patient, as the vagina must be separated from the urinary tract at the time of initial closure.10,32 The native vagina, although often foreshortened, may be adequate to reconstruct at the perineum. Alternatively, creation of a neovagina later in life may be performed through use of large or small bowel.10,55 A review of 5 adult women with cloacal exstrophy demonstrated that 3 were sexually active. Two of the sexually active subjects reported good overall
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sexual satisfaction, despite the presence of a urinary stoma in both. The 2 women who were not sexually active reported reluctance because of genital appearance and presence of a stoma, respectively. One patient had a successful pregnancy and delivered by Cesarean, although this was complicated by perforation of her continent diversion, postpartum uterine prolapse, and development of incontinence from her urinary stoma. In fact, vaginal prolapse was reported in 2 of 5 adult patients and appears to be a frequent problem among females with the exstrophy-epispadias complex.56 There remains a paucity of literature on male sexual function. A review of 8 genotypic male patients who did not undergo gender reassignment and underwent phallic reconstruction demonstrated that all had phallic inadequacy with belowaverage penile length. Sexual histories revealed feelings of sexual inadequacy in all the postpubertal patients. Half of these individuals demonstrated absence of erectile function on nocturnal penile tumescence testing. In the other 2 patients with intact erectile function, one reported difficulty with vaginal penetration secondary to inadequate penile length, while the other was married and able to engage in successful vaginal intercourse.57 Although it is difficult to make definitive recommendations or conclusions based on these small studies, it is clear that considerations of sexual function outcomes must be included in the management of cloacal exstrophy.
Conclusions Cloacal exstrophy remains a rare and challenging diagnosis. Advances in medical and surgical management have allowed for dramatically improved survival and continence rates. However, the chronic nature of cloacal exstrophy must be emphasized. Afflicted patients generally require multiple surgical procedures and will clearly face medical, psychological and social challenges throughout their lives. It is therefore important that these individuals and their families remain under the care of a multidisciplinary team of providers who can offer medical care, counseling and lifelong follow up.
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Seminars in Pediatric Surgery, Vol 20, No 2, May 2011 45. Richards DS, Langham MR Jr, Mahaffey SM. The prenatal ultrasonographic diagnosis of cloacal exstrophy. J Ultrasound Med 1992;11: 507-10. 46. Meizner I, Levy A, Barnhard Y. Cloacal exstrophy sequence: An exceptional ultrasound diagnosis. Obstet Gynecol 1995;86:446-50. 47. Hamada H, Takano K, Shiina H, et al. New ultrasonographic criterion for the prenatal diagnosis of cloacal exstrophy: Elephant trunk-like image. J Urol 1999;162:2123-4. 48. Gobbi D, Fascetti-Leon F, Tregnaghi A, et al. Early prenatal diagnosis of cloacal exstrophy with fetal magnetic resonance imaging. Fetal Diagn Ther 2008;24:437-9. 49. Woo LL, Thomas JC, Brock JW. Cloacal exstrophy: A comprehensive review of an uncommon problem. J Pediatr Urol 2010;6:102-11. 50. Lund DP, Hendren WH. Cloacal exstrophy: Experience with 20 cases. J Pediatr Surg 1993;28:1368-9. 51. Tank ES, Lindenauer SM. Principles of management of exstrophy of the cloaca. Am J Surg 1970;119:95-8. 52. Diamond DA, Burns JP, Mitchell C, et al. Sex assignment for newborns with ambiguous genitalia and exposure to fetal testosterone: Attitudes and practices of pediatric urologists. J Pediatr 2006;148: 445-9. 53. Timsit MO, Mouriquand PE, Ruffion A, et al. Use of forearm free-flap phalloplasty in bladder exstrophy adults. BJU Int 2009;103:1418-21. 54. Stolar CH, Randolph JG, Flanigan LP. Cloacal exstrophy: Individualized management through a staged surgical approach. J Pediatr Surg 1990;25:505-7. 55. Soffer SZ, Rosen NG, Hong AR, et al. Cloacal exstrophy: A unified management plan. J Pediatr Surg 2000;35:932-7. 56. Mathews RI, Gan M, Gearhart JP. Urogynaecological and obstetric issues in women with the exstrophy-epispadias complex. BJU Int 2003;9:845-9. 57. Husmann DA, McLorie GA, Churchill BM. Phallic reconstruction in cloacal exstrophy. J Urol 1989;142:563-4.