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Newman, W. Bladder Exstrophy Epispadias Complex. Encyclopedia. Available online: https://encyclopedia.pub/entry/12836 (accessed on 19 April 2024).
Newman W. Bladder Exstrophy Epispadias Complex. Encyclopedia. Available at: https://encyclopedia.pub/entry/12836. Accessed April 19, 2024.
Newman, William. "Bladder Exstrophy Epispadias Complex" Encyclopedia, https://encyclopedia.pub/entry/12836 (accessed April 19, 2024).
Newman, W. (2021, August 05). Bladder Exstrophy Epispadias Complex. In Encyclopedia. https://encyclopedia.pub/entry/12836
Newman, William. "Bladder Exstrophy Epispadias Complex." Encyclopedia. Web. 05 August, 2021.
Bladder Exstrophy Epispadias Complex
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This entry is adapted from the peer-reviewed paper 10.3390/genes12081149

The bladder exstrophy–epispadias complex (BEEC) is an abdominal midline malformation comprising a spectrum of congenital genitourinary abnormalities of the abdominal wall, pelvis, urinary tract, genitalia, anus, and spine. The vast majority of BEEC cases are classified as non-syndromic and the etiology of this malformation is still unknown.

BEEC bladder exstrophy epispadias cloacal exstrophy

1. Introduction

Congenital anomalies of the lower urinary tract (CALUT) are a group of birth defects of the ureter, bladder, and urethra, which includes bladder exstrophy–epispadias complex (BEEC, MIM #600057). BEEC is an abdominal midline malformation comprising a spectrum of congenital genitourinary abnormalities of the abdominal wall, pelvis, urinary tract, genitalia, anus, and spine [1]. The severity of BEEC ranges from epispadias (E), representing the mildest form to include classic bladder exstrophy (CBE), and extending to cloacal exstrophy (CE), the latter complex—previously referred to as OEIS (omphalocele, exstrophy, imperforate anus, and spinal defects)—being the most severe [1][2]. BEEC is further subdivided into “classic/typical” forms (E, CBE, and CE) and “atypical” forms (duplicated exstrophy, covered exstrophy, and pseudo-exstrophy) [1][3]. In the majority of cases, BEEC is non-syndromic (that is, it is not associated with other congenital birth malformations). The etiology of this malformation is still unknown. Theories have proposed an abnormal overdevelopment of the cloacal membrane preventing medial migration of mesenchyme between the ectodermal and endodermal layers of the lower abdominal wall, resulting in abnormal development of the lower abdominal wall [4] or the involvement of cloacal membrane and mesenchymal tissues during their defective embryogenesis [5][6].

2. Evidence of a Genetic Basis to BEEC

The vast majority of BEEC cases are non-syndromic, however, a number of cases have been reported whereby BEEC has also been associated with various other syndromes, malformations, and congenital diseases (Table 1). There are a number of reported cases of OEIS (CE) with multiple cardiac malformations [7][8][9]. A population study undertaken by Kallen et al., 2000 [10] of 5260 infants with multiple malformations identified 194 infants with OEIS, however, no association with cardiac defects was detected.
Table 1. BEEC and associated birth defects adapted from Ludwig et al., 2009 [11].
Type Type of BEEC OMIM
BEEC-associated syndromes
Al Awadi/Raas-Rothschild syndrome CBE 276820
Acrorenal syndrome CBE 102520
Duane’s syndrome CBE 126800
Elis-van Creveld Syndrome E 225500
Epidermolysis bullosa junctionalis CBE 226650
Epstein syndrome CE 153650
Fraser syndrome Pseudoexstrophy 219000
Goldenhar syndrome CE 164210
Goltz-Gorlin syndrome CE 228250
Gollop-Wolfgang complex CE 305600
Microcephalic osteodysplastic primordial dwarfism type III CBE 210730
Oculoectodermal syndrome CBE 600268
Opitz G/BBB syndrome CBE 145410
BEEC associations
Axial mesodermal dysplasia CE 608160
Caudal dysplasia CBE 600145
VATER association CBE 192350
BEEC-associated Malformations
Head and neck
Chiari I malformation CE 118420
Frontonasal dysplasia CE 136760
Otocephaly-holoprosencephaly CE 202650
Posterior cleft palate CE 119540
Severe early-onset hearing loss CE 561000
Skeletal
Bilateral club feet CE 119800
Severe lower limb defects CE -
Right thumb hypoplasia CE -
Cardiovascular
Duplication of vena cava CE -
DORV, PV-atresia, right-sided aortic arch with PDA Covered CBE 217095
Abdomen
Gastroschisis CBE 230750
Gastroschisis Pseudoexstrophy 230750
BEEC, bladder-exstrophy-epispadias complex; CBE, classic bladder exstrophy; E; epispadias; CE, exstrophy of the cloaca; DORV, double outlet right ventricle; PV, pulmonic valve; PDA, patent ductus arteriosus.
The majority of individuals affected by BEEC have no positive family history of BEEC. However, even though familial occurrence is rare, 30 multiplex families have been described [11][12][13][14]. A number of these appear to follow a Mendelian mode of inheritance. However, in the majority of affected individuals, the genetic basis of BEEC is consistent with a multifactorial etiology [15]. In the majority of multiplex families, only two members are affected. Two families have been reported with three affected members, including males and females with differing degrees of BEEC severity [11]. Reutter et al., 2003 [12] described a unique Moroccan family of three males (two cousins and a maternal uncle) being affected with CBE. In these rare multiplex families, the inheritance of BEEC would be consistent with autosomal dominant with reduced penetrance, autosomal recessive, or X-linked patterns [12]. The lack of recurrence may in part be due to reduced reproductive fitness. This may change due to surgical advances and improvements in reproductive medicine facilitating the birth of children to affected individuals. Studies have shown that individuals with CBE with non-consanguineous and non-affected parents have a recurrence risk among siblings from 0.3 to 2.3% [16][17]. The recurrence risk for offspring from affected parents is 1.4%. The risk of having a second affected child from non-consanguineous and non-affected parents shows an approximate 400-fold increase compared to the general population [16].
Reutter et al., 2007 [14] reported higher concordance rates in monozygotic twins (62%) compared to dizygotic twins (11%) with BEEC, supporting a genetic etiology. A number of reports have shown recurrence of CE within families [18]; an increased occurrence in conjoined and monozygotic twins [19][20][21][22][23][24][25]; concordant conjoined twins [26], and discordant dizygotic twins [6]. Xu et al., 2020 [27] reported CE in twins (n = 28) and triplets (n = 2), including monozygotic (n = 20), dizygotic (n = 3), trizygotic (n = 2), and unknown zygosity (n = 5). Of the CE anomalies within the 20 monozygotic twins, 9 were concordant and 11 were discordant. The higher incidence of CE in monozygotic twins compared to dizygotic twins could suggest a possible genetic contribution to the occurrence of these anomalies. Fullerton et al., 2017 [28] reported that approximately 14% of CE cases occurred in same-sex twins, which supported their hypothesis that the embryogenesis of CE could be related to errors in monozygotic splitting.

3. Conclusions

The application of array-based, GWAS, and next generation sequencing techniques in large BEEC cohorts has helped to identify putative disease-causing genes and chromosomal regions in the human genome for both Mendelian and multifactorial BEEC. Functional analysis of embryonic pathways provides a better understanding of the molecular biological mechanisms underlying normal, urorectal, and genitourinary malformations within the embryology of the human urogenital system.
It is reasonable to propose that both inherited and de novo highly penetrant variants could be relevant to the etiology of BEEC as they have been shown for many genetically heterogeneous congenital birth defects such as congenital heart disease.
New approaches such as gene and pathway enrichment analyses of high-impact de novo variants from whole exome or whole genome data in parent-offspring trios will likely aid in the identification of novel genes and/or pathways to better understand the underlying genetic mechanisms of BEEC, and the potential to use these data to develop therapeutic approaches to help children affected by this devastating congenital disorder.

References

  1. Gearhart, J.P. Exstrophy, Epispadias, and other Bladder Anomalies. In Campbell’s Urology, 8th ed.; Walsh, P.C., Wein, A.J., Vaughan, E.D., Retik, A.B., Eds.; Saunders: Philadelphia, PA, USA, 2002; pp. 2136–2196.
  2. Carey, J.C. Exstrophy of the cloaca and the OEIS complex: One and the same. Am. J. Med. Genet. 2001, 99, 270.
  3. Ebert, A.K.; Reutter, H.; Ludwig, M.; Rösch, W.H. The exstrophy-epispadias complex. Orphanet. J. Rare Dis. 2009, 4, 23.
  4. Marshall, V.F.; Muecke, E.C. Variations in exstrophy of the bladder. J. Urol. 1962, 88, 766–796.
  5. Mildenberger, H.; Kluth, D.; Dziuba, M. Embryology of bladder exstrophy. J. Pediatr. Surg. 1988, 23, 166–170.
  6. Bruch, S.W.; Adzick, N.S.; Goldstein, R.B.; Harrison, M.R. Challenging the embryogenesis of cloacal exstrophy. J. Pediatr. Surg. 1996, 31, 768–770.
  7. Sadula, S.R.; Kanhere, S.V.; Phadke, V.D. Exstrophy of Cloaca Sequence (OEIS Complex) with Multiple Cardiac Malformations. Indian J. Case Rep. 2019, 5, 317.
  8. Batra, P.; Saha, A.; Vilhekar, K.Y.; Gupta, A. OEIS complex with major cardiac malformation: A case report. Indian J. Pathol. Microbiol. 2007, 5, 365–366.
  9. Kant, S.G.; Bartelings, M.M.; Kibbelaar, R.E.; Van Haeringen, A. Severe cardiac defect in a patient with the OEIS complex. Clin. Dysmorphol. 1997, 6, 371–374.
  10. Källen, K.; Castilla, E.E.; Robert, E.; Mastroivacovo, P.; Källe, P. OEIS complex a population study. Am. J. Med Genet. 2000, 92, 62–68.
  11. Ludwig, M.; Ching, B.; Reutter, H.; Boyadjiev, S.A. Bladder exstrophy-epispadias complex. Birth Defects Res. A Clin. Mol. Teratol. 2009, 85, 509–522.
  12. Reutter, H.; Shapiro, E.; Gruen, J.R. Seven new cases of familial isolated bladder exstrophy and epispadias complex (BEEC) and review of the literature. Am. J. Med. Genet. A 2003, 120, 215–221.
  13. Ludwig, M.; Utsch, B.; Reutter, H. Genetic and molecular biological aspects of the bladder exstrophy-epispadias complex (BEEC). Urologe A 2005, 44, 1037–1038, 1040–1044.
  14. Reutter, H.; Qi, L.; Gearhart, J.P.; Boemers, T.; Ebert, A.K.; Rösch, W.; Ludwig, M.; Boyadjiev, S.A. Concordance analyses of twins with bladder exstrophy-epispadias complex suggest genetic etiology. Am. J. Med. Genet. A 2007, 143, 2751–2756.
  15. Boyadjiev, S.A.; Dodson, J.L.; Radford, C.L.; Ashrafi, G.H.; Beaty, T.H.; Mathews, R.; Broman, K.W.; Gearhart, J.P. Clinical and molecular characterization of the bladder exstrophy-epispadias complex: Analysis of 232 families. BJU Int. 2004, 94, 1337–1343.
  16. Shapiro, E.; Lepor, H.; Jeffs, R.D. The inheritance of the exstrophy-epispadias complex. J. Urol. 1984, 132, 308–310.
  17. Messelink, E.J.; Aronson, D.C.; Knuist, M.; Heij, H.A.; Vos, A. Four cases of bladder exstrophy in two families. J. Med. Genet. 1994, 31, 490–492.
  18. Smith, N.M.; Chambers, H.M.; Furness, M.E.; Haan, E.A. The OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects): Recurrence in sibs. J. Med. Genet. 1992, 29, 730–732.
  19. Redman, J.F.; Seibert, J.J.; Page, B.C. Cloacal exstrophy in identical twins. Urology 1981, 17, 73–74.
  20. McLaughlin, J.F.; Marks, W.M.; 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, 721–727.
  21. Lee, D.H.; Cottrell, J.R.; Sanders, R.C.; Meyers, C.M.; Wulfsberg, E.A.; Sun, C.C. OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects) in monozygotic twins. Am. J. Med. Genet. 1999, 84, 29–33.
  22. Goldfischer, E.R.; Almond, P.S.; Statter, M.B.; Miller, G.; Arensman, R.M.; Cromie, W.J. Omphalopagus twins with covered cloacal exstrophy. J. Urol. 1997, 157, 1004–1005.
  23. Casale, P.; Grady, R.W.; Waldhausen, J.H.; Joyner, B.D.; Wright, J.; Mitchell, M.E. Cloacal exstrophy variants. Can blighted conjoined twinning play a role? J. Urol. 2004, 172, 1103–1106.
  24. Siebert, J.R.; Rutledge, J.C.; Kapur, R.P. Association of cloacal anomalies, caudal duplication, and twinning. Pediatr. Dev. Pathol. 2005, 8, 339–354.
  25. Tihtonen, K.; Lagerstedt, A.; Kähkönen, M.; Kirkinen, P. Diamniotic omphalopagus conjoined twins in a diamniotic pregnancy. Fetal Diagn. 2009, 25, 343–345.
  26. Métneki, J.; Czeizel, A. Conjoined twins in Hungary, 1970–1986. Acta Genet. Med. Gemellol. Roma 1989, 38, 285–299.
  27. Xu, Y.Q.; Chen, X.L.; Zhao, S.; Chen, P.W.; Yin, X.M.; Xiong, S.Y.; Ding, Z.; Xiong, F.; Yang, X.H. OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects) in monozygotic twins: A case report and literature review. Clin. Exp. Obstet. Gynecol. 2020, 47, 154–158.
  28. Fullerton, B.S.; Sparks, E.A.; Hall, A.M.; Velazco, C.S.; Modi, B.P.; Lund, D.P. High prevalence of same-sex twins in patients with cloacal exstrophy: Support for embryological association with monozygotic twin. J. Pediatr. Surg. 2017, 52, 807.
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