Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5514_Библиотеки_им_академика_М_И_Перельмана.pdf
24
40. Lowentritt BH, Van Zijl PS, Frimberger D, Baird A, Lakshmanan Y, Gearhart JP.Variants of
the exstrophy complex: a single institution experience. J Urol. 2005;173(5):1732–7.
41. Mallmann MR, Reutter H, Muller A, Boemers TM, Geipel A, Berg C, etal. Prenatal diagnosis
of covered cloacal exstrophy. Fetal Diagn Ther. 2014;36(4):333–6.
42. Ozcan T, Woo L, Wien M, Lazebnik N.Prenatal ultrasound ndings of covered bladder exstrophy and persistent cloaca. J Clin Ultrasound. 2021;49(8):834–7.
43. Vinit N, Glenisson M, Chalouhi G, Salomon LJ, Millischer-Bellaiche AE, Beaudoin S, etal.
Prenatal diagnosis of unusual variant of exstrophy-epispadias complex. Ultrasound Obstet
Gynecol. 2023;62(1):155–6.
44. Reutter H, Holmdahl G.Genetic counseling for bladder exstrophy-epispadias complex. Eur J
Pediatr Surg. 2021;31(6):468–71.
45. Draaken M, Baudisch F, Timmermann B, Kuhl H, Kerick M, Proske J, etal. Classic bladder
exstrophy: frequent 22q11.21 duplications and denition of a 414 kb phenocritical region.
Birth Defects Res A Clin Mol Teratol. 2014;100(6):512–7.
46. Pitsava G, Feldkamp ML, Pankratz N, Lane J, Kay DM, Conway KM, etal. Exome sequencing of child-parent trios with bladder exstrophy: ndings in 26 children. Am J Med Genet
A. 2021;185(10):3028–41.
47. Kollges R, Stegmann J, Schneider S, Waffenschmidt L, Fazaal J, Breuer K, etal. Exome survey
and candidate gene re-sequencing identies novel exstrophy candidate genes and implicates
LZTR1in disease formation. Biomolecules. 2023;13(7):1117.
48. Jelin AC, Wohler E, Martin R, Di Carlo H, Isaacs W, Ko J, etal. De novo variants identied
by trio whole exome sequencing of bladder exstrophy epispadias complex. Am J Med Genet
A. 2024;194(4):e63501.
J. Gebb et al.
Bladder Exstrophy Genetics: Our Current Understanding
JohnK.Weaver andChen-HanWilfredWu
Bladder Exstrophy Genetics
Bladder exstrophy is a devastating congenital abnormality of the urinary tract in
which infants are born with the urinary bladder extruded through their abdominal
wall, a urethra that is open dorsally, and signicant secondary abnormalities of the
genitalia. While the etiology of bladder exstrophy is not known, a clear genetic
component has been highlighted.
Epidemiologic andObservational Studies
In 1984, using survey data, Shapiro etal. found that bladder exstrophy recurred in 9
of approximately 2500 families (1in 275) who already had a history of bladder
exstrophy or complete epispadias [17]. This is a far higher rate than is seen in the
general population (approximately 1in 10,000–100,000) [9]. Shapiro et al. also
found that 3 of 215 offspring from patients with bladder exstrophy or epispadias
inherited bladder exstrophy or epispadias, i.e., at an even higher rate of 1in 70 live
births. Finally, they identied 17 sets of twins where at least 1 of the twins was
affected by bladder exstrophy. Bladder exstrophy did not occur in both members of
any of the ve sets of fraternal twins. Both members of identical male twins were
affected with exstrophy in ve monozygotic pairs, whereas only one member of the
three pairs of identical female twins was affected. Information on gender or twin
3
J. K. Weaver (*)
Cleveland Clinic Lerner College of Medicine at Case Western Reserve University School of
Medicine, Cleveland, OH, USA
e-mail: weaverj3@chop.edu
C.-H. W. Wu
Case Western Reserve University School of Medicine, Cleveland, OH, USA
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
A. R. Shukla, R. S. Joshi (eds.), Bladder Exstrophy and Epispadias,
https://doi.org/10.1007/978-3-031-91238-2_3
25
26
J. K. Weaver and C.-H. W. Wu
type was unavailable in four cases [17]. In a separate study, Lattimer and Smith
cited a set of identical twins with bladder exstrophy and another set of twins in
whom only one child had exstrophy [18].
In another study using survey data, Ives etal. followed the families of 102 index
patients with bladder exstrophy treated at The Hospital for Sick Children, Great
Ormond Street. Of the 102 patients, 97 had BE and 5 had cloacal exstrophy. In all
they had 162 siblings, none of whom had bladder exstrophy. They concluded that
the risk to siblings is low and probably less than 1% [8].
In 2003, Reutter etal., in conjunction with Shapiro, published seven new cases
of familial isolated bladder exstrophy and epispadias complex (BEEC). The seven
new families were noteworthy for their cumulative patterns of inheritance and the
genetic implications. In six pedigrees, two family members were affected: two siblings, two 3rd-degree cousins, and two uncle–nephew pairs. This pattern is more
suggestive of a complex inheritance, pointing toward polygenic with an environmental component, as opposed to conventional Mendelian inheritance. There were
a total of 13 probands in these families, comprised of 10 males and 3 females, for a
male-to-female ratio of 3.3:1. Probands in four families had the identical classical
bladder exstrophy phenotype. In two families, one proband had bladder exstrophy
and the other epispadias. The family with a single proband had epispadias [16].
In 2004, Boyadjiev etal., from a cohort of 285 families with BEEC, obtained
epidemiological information from 151 families [2]. They also performed a detailed
clinical genetic examination of 94 probands. In all, 440 DNA samples were collected from 163 families for cytogenetics and molecular analysis. Karyotype analysis on 37 cases detected two chromosomal abnormalities, i.e., 46XY t(8;9)
(p11.2;q13) and 47XYY. Molecular analysis of the HLXB9 gene, which causes
Currarino syndrome (sacral fusion abnormality), did not detect pathogenic variants
in the blood or bladder DNA of ten patients with bladder or cloacal exstrophy. From
this analysis, the authors concluded BEEC most commonly occurs as an isolated
sporadic birth defect with a recurrence risk of less than 1%. There was no evidence
of a single-gene effect or common environmental factor in this study population.
However, there was a statistically signicant association with advanced parental age.
The following year, Boyadjiev etal. reported on their patient with sporadic bladder exstrophy and de novo apparently balanced chromosomal translocation
46,XY,t(8;9)(p11.2;q13) [2]. This was analyzed by uorescence in situ hybridization (FISH) and molecular methods, and they were able to map both translocation
breakpoints to single genomic clones. The chromosome 8p11.2 breakpoint was
mapped to bacterial articial chromosome (BAC) clone RP4-547J18, predicted to
contain several hypothetical genes. Characterization of the chromosome 9q13
breakpoint indicated a disruption in the 5′ region of CNTNAP3 within BAC
RP11-292B8. This observation suggested possible involvement of CNTNAP3in the
etiology of bladder exstrophy. Additionally, FISH analysis identied several
genomic copies of CNTNAP3 on both sides of the chromosome 9 centromere anking the polymorphic heterochromatin. Northern blot analysis of lymphoblast and
bladder tissue RNA conrmed CNTNAP3 transcripts in these tissues and did not
show abnormal CNTNAP3 expression in the proband and two unrelated patients
3 Bladder Exstrophy Genetics: Our Current Understanding
27
with bladder exstrophy. The authors concluded that CNTNAP3 and/or other genes
on chromosome 9q13 or chromosome 8p11.2 may contribute to the etiology of
BEEC.They also identied multiple copies of three BAC clones, indicating that
segmental duplications of the pericentric region of chromosome 9 and its anking
genes have occurred due to a combination of repeated pericentric inversions and
unequal crossing over during evolution.
An increased rate of BEEC in IVF pregnancies has been reported. Wood etal. in
2007 found that under the hypothesis of no association between IVF and BEEC, the
expected incidence of IVF in BEEC children ranged between 0.60% and 1.59%
[21]. However, the observed incidence of IVF in BEEC children evaluated at Johns
Hopkins University ranged between 4.2% and 6.7%. Comparison of the expected
and observed incidence using a Pearson-type chi-squared test resulted in a bootstrapped P value of 0.0182. The authors concluded that the incidence of IVF in
BEEC children appears to be higher than what would be expected if there was no
association between IVF and BEEC.
Advanced Genetic Technology andMethods
Strides have been made in recent years with respect to identifying candidate genes.
Multiple studies have utilized advanced genetic technology and methods. In 2008,
Ludwig etal. sought to identify genetic risk loci using parametric and nonparametric linkage analysis, searching for homozygous segments and more complex inherited loci, respectively [10]. Two pedigrees, Spanish and German, each comprising
two members affected with classic bladder exstrophy, were analyzed by genomewide linkage scan. They identied evidence for possible risk/modifying loci on
chromosomes 2p22.1–p21, 2p25.2–p25.1, 4q23–q32.3, 7q21.3–q33, 7q34–q36.1,
14q31.1–q32.2, and 19q13.33–q13.43 (LOD scores >1.50). This study was the rst
positional approach to identify chromosomal candidate regions causally related to
BEEC.Their results suggested the presence of causal genes in the regions identied, but the authors concluded that these regions needed further validation in future
studies.
A murine p63+/+ knockout model showed the full picture of classic exstrophy
of the bladder and other urogenital defects within the BEEC spectrum. This led
Ching etal. to study in depth the role of p63in urogenital development in mice and
the implication of p63in human BEEC.They performed whole mount in situ analysis in mice to investigate the ventro-caudal expression of the p63 transcript at
gestational days (GD) 9.5–12.5, the equivalent of human gestational weeks 4–6,
which is the postulated time of BEEC organogenesis in humans [3]. In addition,
p63 expression analysis was performed in human blood and bladder tissue of 15
BEEC newborns, accompanied by sequencing analysis of their genomic DNA.They
also conducted sequencing analysis of genomic DNA in an additional 22 BEEC
patients. In mouse embryos, p63 expression was detected at days 9.5–12.5in the
cloacal membrane and urethral epithelium, supporting its role in the morphogenesis of the external genitalia and the bladder. Tissue-specic expression of a novel
28
J. K. Weaver and C.-H. W. Wu
and already-known mRNA isoforms was established, and a reproducible dysregulation of variable p63 isoforms was observed in 11 of 15 patients, indicating altered
gene expression. However, no obvious p63 gene mutations were identied in any
of the patients. The authors concluded that these results strongly suggest that p63
is not only involved in embryonic formation of the urogenital and ventrocaudal
anatomy but is also highly dysregulated in human BEEC bladder tissue. They
hypothesized that since p63 has been shown to self-regulate its expression through
a balance of its isoforms, the dysregulation observed may contribute to the formation of BEEC.In 2013, Qi etal. conducted a candidate gene association study to
further investigate the role of p63in BEEC [15]. They conducted a family-based
association study of p63 using 154 Caucasian patients with BEEC and their unaffected parents. High-throughput single nucleotide polymorphism (SNP) genotyping was carried out for 109 selected tagging SNPs localized within p63 with a
minor allele frequency>0.01. Individual and haplotype SNP transmission disequilibrium tests were conducted using Plink and Haploview, respectively. Nominally
signicant associations were identied between BEEC and six SNPs, and four
haplotype blocks include or are near these signicant SNPs. They also examined
parent-of-origin effects using paternal asymmetry tests. Analysis of parent-of-origin effects showed signicant results for seven SNPs. None of these results
remained signicant after multiple testing corrections. The authors concluded that
the altered transmission of p63 variants in BEEC patients may be suggestive of its
involvement in the disease etiology.
Copy Number Variant (CNV) Studies
Multiple array-based genome-wide CNV studies for BEEC have been performed.
An early study from Draaken etal. identied a de novo 0.9Mb microduplication on
chromosome 19p13.12in a single BE patient [5]. In another study, Draaken etal.
identied duplications in 22q11.21. Two other studies that included a total of 102
BE patients identied a duplication of 22q11.21in four individuals [4, 11]. An addi-
tional case report described an array-based CNV analysis in a single CBE patient
with a duplication of 22q11.21 [14].
Following their array-based genome-wide CNV studies, Draaken etal. used a
multiplex ligation-dependent probe amplication (MLPA)-based approach to perform a regional screen for 22q11.21 duplications in 244 independent BEEC patients.
The authors identied four novel duplications of variable size in four unrelated BE
patients [6].
To detect further CNVs, von Lowtzow etal. performed an array analysis on 169
BEEC patients [20]. Following the application of stringent lter criteria, seven rare
CNVs were identied. These CNVs ranged from 1 to 6.08Mb in size. To identify
smaller CNVs, relaxed lter criteria used in the detection of previously reported
BEEC-associated chromosomal regions were applied. This resulted in the identication of six additional rare CNVs. These CNVs ranged from 0.03 to 0.08Mb in
size. For 10 of these 13 CNVs, conrmation and segregation analyses were
3 Bladder Exstrophy Genetics: Our Current Understanding
29
performed (5 of maternal origin; 5 of paternal origin). Interestingly, one female with
classic bladder exstrophy carried a 1.18Mb duplication of 22q11.1.
In 2023, Nordenskjold etal., citing that there is a clear genetic background with
chromosome aberrations but so far no consistent ndings apart from 22q11 duplications detected in about 2–3% of all patients, performed chromosomal microarray
analysis on a cohort of 140 persons born with BE to look for submicroscopic chromosomal deletions and duplications [13]. Pathogenic or possibly pathogenic microdeletions or duplications were found in 16 patients (11.4%) and 9 with unknown
signicance. Two ndings were in known syndromic regions
(chr16:29645396–30168276 and chrX:154822249–155197455).
Most recently, in 2025, Weaver et al. presented ndings of their array-based
genome-wide CNV studies [19]. This study was unique in that it was the rst genetic
analysis of BEEC patients of non-European origin. The cohort included 57 patients
of European origin and 93 patients of South Asian origin. The authors identied a
total of 38 CNVs of statistical signicance following ltering using ParseCNV.This
study revealed numerous CNVs that had not been reported previously. Of note, they
identied a CNV deletion at chr16:28635133–28636902, which was near one of the
CNVs Nordenskjold et al. identied in a known syndromic region
(chr16:29645396–30168276).
Gene Expression Studies
In 2011, Qi etal. used genome-wide expression proling to identify 162 BEEC
candidate genes that have twofold or higher expression differences between exstrophic and normal bladder smooth muscles in mouse and human embryologic bladder tissues [15]. They also found 16 candidate genes that are expressed in the
infraumbilical endoderm and mesoderm. Most of these genes have functions related
to cellular assembly, musculoskeletal system development, and connective tissue
morphology. Specically, 30% of these genes were related to the desmosomal structure and cytoskeleton assembly, of which 69% were under-expressed in exstrophic
bladders. In this study, the two most downregulated genes in exstrophic bladders,
DES (DESMIN) and SYNM (DESMUSLIN), encode muscle-specic proteins that
interact with DSP (DESMOPLAKIN), the sixth most overexpressed gene in exstrophic bladders.
In 2018, Ching etal. reported that deletion of Isl1 from the genital mesenchyme
in mice led to hypoplasia of the genital tubercle and prepuce, with an ectopic urethral opening and epispadias-like phenotype [3]. These mice also developed hydroureter and hydronephrosis. Identication of ISL1 transcriptional targets via
ChIP-Seq and expression analyses revealed that Isl1 regulates several important
signaling pathways during embryonic genital development, including the BMP,
WNT, and FGF cascades. An essential function of Isl1 during development of the
external genitalia is to induce Bmp4-mediated apoptosis in the genital mesenchyme.
Together, these studies demonstrated that Isl1 plays a critical role during development of the external genitalia and potentially formed the basis for a greater
30
J. K. Weaver and C.-H. W. Wu
understanding of the molecular mechanisms underlying the pathogenesis of BEEC
and urinary tract defects in humans.
Genome-wide Association Study (GWAS)
A genome-wide association study (GWAS) meta-analysis combining 568 BE
patients and 3241 controls of European origin identied an association with a locus
containing the transcriptional enhancer ISL1 (p=2.22×10 − 8) [7]. Further functional and model organism studies reinforced a possible causal role for ISL1 in
BE.For example, developmental biology models were used to clarify the location
of ISL1 activity in the forming urinary tract, and genetic lineage analysis of ISL1expressing cells by a lineage tracer mouse model showed ISL1-expressing cells in
the urinary tract of mouse embryos [1, 22].
In a follow-up to their prior GWAS study that identied ISL1 as a candidate gene,
Mingardo etal. published a GWAS meta-analysis of 628 patients with BE and 7352
ethnically matched controls comprising seven independent cohorts [12]. In this
study they redemonstrated the signicance of their previously identied ISL1-
containing loci and identied seven novel genome-wide loci of signicance. In
these regions reside ten coding and four non-coding genes. Among the coding genes
was EFNA1, which is strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequencing of EFNA1 in the investigated classic
bladder exstrophy cohort displayed an enrichment of rare protein-altering mutations
at a statistically signicant higher rate than the general population. Additionally,
they showed that all coding genes were expressed and/or signicantly regulated in
both mouse and human embryonic developmental bladder stages. Finally, nine of
the coding genes residing in the regions of genome-wide signicance were differentially expressed in bladder cancers. The authors postulated that differential expression turns these developmental genes on later in life and that these genes may play
a role in the known bladder cancer susceptibility of BE patients. Similar to Mingardo
etal., Weaver etal. found that a high percentage of our regions of interest include
genes with known cancer associations. In our CNV study of a European and South
Asian cohort, 10 of the 23 duplication CNVs and 6 of the 18 deletion CNVs contain
genes with known cancer associations. However, the genes Weaver etal. identied
did not overlap with the genes identied by Mingardo etal. Further investigation
will be needed to better dene the associations between the genes implicated in
bladder exstrophy and cancer, as they could provide insight into methods for cancer
prevention in this population.
Future Directions
Overall, the genetic analysis of bladder exstrophy is still in its infancy. Due to the
rare nature of this disease, future collaborations across research groups will be
needed to make signicant strides in gaining a more complete understanding of the
3 Bladder Exstrophy Genetics: Our Current Understanding
31
genetic underpinnings of bladder exstrophy. Almost all published studies to date,
with the exception of one, include only European populations. Studies including
non-European populations will be particularly critical to furthering our understanding in the future.
References
1. Arkani S, Cao J, Lundin J, Nilsson D, Källman T, Barker G, Holmdahl G, Clementsson
Kockum C, Matsson H, Nordenskjöld A. Evaluation of the ISL1 gene in the pathogenesis
of bladder exstrophy in a Swedish cohort. Hum Genome Var. 2018;5:18009. https://doi.
org/10.1038/hgv.2018.9.
2. Boyadjiev SA, Dodson JL, Radford CL, Ashra GH, Beaty TH, Mathews RI, Broman
KW, Gearhart JP. Clinical and molecular characterization of the bladder exstrophyepispadias complex: analysis of 232 families. BJU Int. 2004;94(9):1337–43. https://doi.
org/10.1111/j.1464- 410X.2004.05170.x.
3. Ching ST, Infante CR, Du W, Sharir A, Park S, Menke DB, Klein OD.Isl1 mediates mesenchymal expansion in the developing external genitalia via regulation of Bmp4, Fgf10 and Wnt5a.
Hum Mol Genet. 2018;27(1):107–19. https://doi.org/10.1093/hmg/ddx388.
4. Draaken M, Reutter H, Schramm C, Bartels E, Boemers TM, Ebert A-K, Rösch W, Schröder
A, Stein R, Moebus S, Stienen D, Hoffmann P, Nöthen MM, Ludwig M.Microduplications
at 22q11.21 are associated with non-syndromic classic bladder exstrophy. Eur J Med Genet.
2010;53(2):55–60. https://doi.org/10.1016/j.ejmg.2009.12.005.
5. Draaken M, Mughal SS, Pennimpede T, Wolter S, Wittler L, Ebert A-K, Rösch W, Stein R,
Bartels E, Schmidt D, Boemers TM, Schmiedeke E, Hoffmann P, Moebus S, Herrmann BG,
Nöthen MM, Reutter H, Ludwig M.Isolated bladder exstrophy associated with a de novo
0.9Mb microduplication on chromosome 19p13.12. Birth Defects Res A Clin Mol Teratol.
2013;97(3):133–9. https://doi.org/10.1002/bdra.23112.
6. Draaken M, Baudisch F, Timmermann B, Kuhl H, Kerick M, Proske J, Wittler L, Pennimpede
T, Ebert A-K, Rösch W, Stein R, Bartels E, von Lowtzow C, Boemers TM, Herms S, Gearhart
JP, Lakshmanan Y, Kockum CC, Holmdahl G, etal. Classic bladder exstrophy: frequent
22q11.21 duplications and denition of a 414 kb phenocritical region. Birth Defects Res A
Clin Mol Teratol. 2014;100(6):512–7. https://doi.org/10.1002/bdra.23249.
7. Draaken M, Knapp M, Pennimpede T, Schmidt JM, Ebert A-K, Rösch W, Stein R, Utsch B,
Hirsch K, Boemers TM, Mangold E, Heilmann S, Ludwig KU, Jenetzky E, Zwink N, Moebus
S, Herrmann BG, Mattheisen M, Nöthen MM, etal. Genome-wide association study and metaanalysis identify ISL1 as genome-wide signicant susceptibility gene for bladder exstrophy.
PLoS Genet. 2015;11(3):e1005024. https://doi.org/10.1371/journal.pgen.1005024.
8. Ives E, Coffey R, Carter CO. A family study of bladder exstrophy. J Med Genet.
1980;17(2):139–41. https://doi.org/10.1136/jmg.17.2.139.
9. Ludwig M, Utsch B, Reutter H. Genetic and molecular biological aspects of the bladder
exstrophy-epispadias complex (BEEC). Urologe A. 2005;44(9):1037–8, 1040–1044. https://
doi.org/10.1007/s00120- 005- 0863- z.
10. Ludwig M, Rüschendorf F, Saar K, Hübner N, Siekmann L, Boyadjiev SA, Reutter H.Genomewide linkage scan for bladder exstrophy-epispadias complex. Birth Defects Res A Clin Mol
Teratol. 2009;85(2):174–8. https://doi.org/10.1002/bdra.20512.
11. Lundin J, Söderhäll C, Lundén L, Hammarsjö A, White I, Schoumans J, Läckgren G,
Kockum CC, Nordenskjöld A. 22q11.2 microduplication in two patients with bladder exstrophy and hearing impairment. Eur J Med Genet. 2010;53(2):61–5. https://doi.org/10.1016/j.
ejmg.2009.11.004.
32
12. Mingardo E, Beaman G, Grote P, Nordenskjöld A, Newman W, Woolf AS, Eckstein M,
Hilger AC, Dworschak GC, Rösch W, Ebert A-K, Stein R, Brusco A, Di Grazia M, Tamer
A, Torres FM, Hernandez JL, Erben P, Maj C, etal. A genome-wide association study with
tissue transcriptomics identies genetic drivers for classic bladder exstrophy. Commun Biol.
2022;5(1):1203.
13. Nordenskjöld A, Arkani S, Pettersson M, Winberg J, Cao J, Fossum M, Anderberg M, Barker
G, Holmdahl G, Lundin J.Copy number variants suggest different molecular pathways for
the pathogenesis of bladder exstrophy. Am J Med Genet A. 2023;191(2):378–90. https://doi.
org/10.1002/ajmg.a.63031.
14. Pierquin G, Uwineza A. 22q11.2 microduplication in a patient with bladder exstrophy and
delayed psychomotor development. Eur J Hum Genet. 2012;20(1):89.
15. Qi L, Wang M, Yagnik G, Mattheisen M, Gearhart JP, Lakshmanan Y, Ebert A-K, Rösch W,
Ludwig M, Draaken M, Reutter H, Boyadjiev SA.Candidate gene association study implicates
p63in the etiology of nonsyndromic bladder-exstrophy-epispadias complex. Birth Defects Res
A Clin Mol Teratol. 2013;97(12):759–63. https://doi.org/10.1002/bdra.23161.
16. Reutter H, Shapiro E, Gruen JR. Seven new cases of familial isolated bladder exstrophy and epispadias complex (BEEC) and review of the literature. Am J Med Genet
A. 2003;120A(2):215–21. https://doi.org/10.1002/ajmg.a.20057.
17. Shapiro E, Lepor H, Jeffs RD.The inheritance of the exstrophy-epispadias complex. J Urol.
1984;132(2):308–10.
18. Smith MJ, Lattimer JK. The management of bladder exstrophy. Surg Gynecol Obstet.
1966;123(5):1015–8.
19. Weaver JK, Weiss DA, Thompson A, Joshi R, Ramji J, Shukla AR, D’Souza N, Kim E, Lee
J, Wu CW, Broms R, Glessner J, Mentch F, Hakonarson H, Pyle LC. Genetic analysis of
two bladder exstrophy populations of South Asian and North American origin. J Pediatr Urol.
2025;S1477–5131(25):00234–7. https://doi.org/10.1016/j.jpurol.2025.04.018. Epub ahead of
print. PMID: 40340191.
20. von Lowtzow C, Hofmann A, Zhang R, Marsch F, Ebert A-K, Rösch W, Stein R, Boemers
TM, Hirsch K, Marcelis C, Feitz WFJ, Brusco A, Migone N, Di Grazia M, Moebus S,
Nöthen MM, Reutter H, Ludwig M, Draaken M.CNV analysis in 169 patients with bladder exstrophy-epispadias complex. BMC Med Genet. 2016;17(1):35. https://doi.org/10.1186/
s12881- 016- 0299- x.
21. Wood HM, Babineau D, Gearhart JP.In vitro fertilization and the cloacal/bladder exstrophyepispadias complex: a continuing association. J Pediatr Urol. 2007;3(4):305–10. https://doi.
org/10.1016/j.jpurol.2006.10.007.
22. Zhang R, Knapp M, Suzuki K, Kajioka D, Schmidt JM, Winkler J, Yilmaz Ö, Pleschka M,
Cao J, Kockum CC, Barker G, Holmdahl G, Beaman G, Keene D, Woolf AS, Cervellione RM,
Cheng W, Wilkins S, Gearhart JP, etal. ISL1 is a major susceptibility gene for classic bladder
exstrophy and a regulator of urinary tract development. Sci Rep. 2017;7:42170. https://doi.
org/10.1038/srep42170.
https://doi.org/10.1038/s42003- 022- 04092- 3.
https://doi.org/10.1016/s0022- 5347(17)49605- 4.
J. K. Weaver and C.-H. W. Wu
Prenatal and Postnatal Imaging of the Bladder Epispadias-Exstrophy Complex
EdwardR.Oliver andSusanJ.Back
Introduction
In many countries, the diagnosis of the epispadias-exstrophy complex (EEC) is frequently made through the second-trimester anatomic screening obstetric ultrasound.
Although fetal magnetic resonance imaging (MRI) may not be as readily accessible
as ultrasound, it can be a powerful imaging adjunct in assessing cases of suspected
EEC.Postnatally, imaging is frequently employed to conrm prenatal ndings and
assess for complications—either prior to or after surgical correction—such as urinary obstruction. Ultrasound remains the preferred modality for assessing the genitourinary anatomy in the EEC; however, other modalities, such as MRI, uoroscopy,
and CT, may often be employed. In this chapter, we review the prenatal imaging
features of isolated bladder exstrophy and cloacal exstrophy and briey discuss the
imaging features of the much less common exstrophy variants. In addition, we
review common postnatal imaging ndings and share some of our experience and
tips for performing and interpreting imaging studies at a tertiary pediatric center
that sees a high volume of EEC patients.
4
E. R. Oliver (*)
Department of Radiology and Richard D. Wood Jr. Center for Fetal Diagnosis and Treatment,
Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
e-mail: olivere1@chop.edu
S. J. Back
Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
e-mail: backs@chop.edu
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
A. R. Shukla, R. S. Joshi (eds.), Bladder Exstrophy and Epispadias,
https://doi.org/10.1007/978-3-031-91238-2_4
33