Clinical and molecular characterization of the bladder exstrophy‐epispadias complex: analysis of 232 families

Boyadjiev, Simeon A.; Dodson, Jennifer L.; Radford, Cristi; Ashrafi, Gerald H; Beaty, Terri H.; Mathews, Ranjiv; Broman, Karl W.; Gearhart, John P.

doi:10.1111/j.1464-410x.2004.05170.x

Cited by 80 publications

(99 citation statements)

References 32 publications

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“…Contrary to previous findings describing an overrepresentation of very young mothers of BEEC children 2 but consistent with Boyadjiev et al, 6 we only found two mothers younger than 20 years. Furthermore, we detected no differences in parental age among the different phenotypes.…”

Section: Discussionsupporting

confidence: 88%

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Epidemiological Survey of 214 Families With Bladder Exstrophy-Epispadias Complex

et al. 2008

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Purpose-To identify causative non-genetic and genetic risk factors to the bladder exstrophyepispadias complex (BEEC).Materials and Methods-237 BEEC families were invited to participate and information was obtained from 214 families, mainly comprising European countries.Results-Two families showed familial occurrence. Male predominance (p 0.001) was found among all BEEC subgroups comprising epispadias (E), classical exstrophy of the bladder (CBE) or cloacal exstrophy (CE), with male to female ratios of 1.4, 2.8, and 2.0, respectively. No association with parental age, maternal reproductive history or with periconceptional maternal exposure to alcohol, drugs, chemical noxa, radiation or infections was found. However, periconceptional maternal exposure to smoking (p 0.009) was significantly more common for CE patients than for the combined group of E/CBE patients. Only 16.8% of mothers followed the current recommendations *Correspondence to: Michael Ludwig, Ph.D., Dept. of Clinical Biochemistry and Clinical Pharmacology, University of Bonn, SigmundFreud-Str. 25, D-53105 Bonn, Germany. E-mail: E-mail: mludwig@uni-bonn.de. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of periconceptional folic acid supplementation. 17.6% had started supplementation before the 10 th week of gestation. Interestingly, in the latter group, mothers of CE patients were more compliant (p 0.037) than mothers of the combined group of E/CBE patients. Furthermore, mothers of CE children knew significantly more often prenatally that their child would have a congenital malformation (p < 0.0001) than mothers of E/CBE children.Conclusions-Our study corroborates the hypothesis that E, CBE and CE are causally related, representing a spectrum of the same developmental defect, with a small risk of recurrence within families. Embryonic exposure to maternal smoking appears to enforce the severity, whereas periconceptional folic acid supplementation does not seem to alleviate it. There is a disproportional prenatal ultrasound detection rate between severe and mild phenotypes, possibly due to the neglect of imaging of full urinary bladders with focus on neural tube defects.

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Section: Discussionsupporting

confidence: 88%

“…Due to its low prevalence, epidemiological data on non-genetic risk factors are limited. 6 The present survey represents one of the largest to be conducted among BEEC families to date.…”

Section: Discussionmentioning

confidence: 99%

Epidemiological Survey of 214 Families With Bladder Exstrophy-Epispadias Complex

et al. 2008

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“…There is substantial evidence that genetic factors contribute to the development of these malformations; in particular, CNV studies in sporadic patients have identified de novo events that occur in specific chromosomal regions (Bartels et al, 2011;Boocock & Donnai, 1987;Boyadjiev et al, 2004;Cuschieri & EUROCAT Working Group, 2001;Draaken et al, 2010;Falcone et al, 2007;Keppler-Noreuil, 2001;Ludwig et al, 2009;Marcelis et al, 2011;Schramm et al, 2011aSchramm et al, , 2011bShapiro et al, 1984). We hypothesized that CNVs affecting coding regions that occur after twinning might contribute to discordance in MZ twin pairs with ARM or the BEEC.…”

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confidence: 99%

CNV Analysis in Monozygotic Twin Pairs Discordant for Urorectal Malformations

et al. 2013

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Early post-twinning mutational events can account for discordant phenotypes in monozygotic (MZ) twin pairs. Such mutational events may comprise genomic alterations of different sizes, ranging from single nucleotides to large copy-number variations (CNVs). Anorectal malformations (ARM) and the bladder exstrophy-epispadias complex (BEEC) represent the most severe end of the urorectal malformation spectrum. Recently, CNV studies in patients with sporadic ARM and the BEEC have identified de novo events that occur in specific chromosomal regions. We hypothesized that early arising, post-twinning CNVs might contribute to discordance in MZ twin pairs with ARM or the BEEC; knowledge of such CNVs might help to identify additional chromosomal regions involved in the development of these malformations. We investigated four discordant MZ twin pairs (three ARM and one BEEC) using molecular karyotyping arrays comprising 1,140,419 markers with a median marker spacing of 1.5 kb. Filtering the coding regions for possible disease-causing post-twinning de novo CNVs present only in the affected twin, but not in the unaffected twin or the parents, identified a total of 136 CNVs. These 136 CNVs were then filtered against publicly available databases and finally re-evaluated visually. No potentially causative CNV remained after applying these filter criteria. Our results suggest that post-twinning CNV events that affect coding regions of the genome did not contribute to the discordant phenotypes in MZ twin pairs that we investigated. Possible causes for the discordant phenotypes include changes in regulatory elements or smaller genetic changes within coding regions which may be detectable by whole-exome sequencing.

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“…Prevalence at birth ranges from 1/30,000 for CBE to 1/200,000 for CE (4). There is a greater proportion of affected males than females, ranging from 1.8:1 to 6:1 (5,6). While the etiology of BEEC remains unknown, strong evidence exists linking its development to genetic effects.…”

Section: Introductionmentioning

confidence: 99%

“…Typically, the patients with BEEC do not have developmental delays, and with the exception of CE, there are few anomalies outside of the urogenital system (5,6). The associated anomalies observed in BEEC are mesodermderived, including omphalocele, hernias, kidney agenesis, imperforate anus, and pelvic dysplasia.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide expression profiling of urinary bladder implicates desmosomal and cytoskeletal dysregulation in the bladder exstrophy-epispadias complex

Chen

Hur

et al. 2011

Int J Mol Med

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Abstract. The bladder exstrophy-epispadias complex (BEEC) represents a spectrum of urological abnormalities where part, or all, of the distal urinary tract fails to close during development, becoming exposed on the outer abdominal wall. While the etiology of BEEC remains unknown, strong evidence exists that genetic factors are implicated. To understand the pathways regulating embryonic bladder development and to identify high-probability BEEC candidate genes, we conducted a genome-wide expression profiling (GWEP) study using normal and exstrophic human urinary bladders and human and mouse embryologic bladderprecursor tissues. We identified 162 genes differentially expressed in both embryonic and postnatal human samples. Pathway analysis of these genes revealed 11 biological networks with top functions related to skeletal and muscular system development, cellular assembly and development, organ morphology, or connective tissue disorders. The two most down-regulated genes desmin (DES, fold-change, -74.7) and desmuslin (DMN, fold-change, -53.0) are involved in desmosome mediated cell-cell adhesion and cytoskeletal architecture. Intriguingly, the sixth most overexpressed gene was desmoplakin (DSP, fold-change, +48.8), the most abundant desmosomal protein. We found 30% of the candidate genes to be directly associated with desmosome structure/ function or cytoskeletal assembly, pointing to desmosomal and/or cytoskeletal deregulation as an etiologic factor for BEEC. Further findings indicate that p63, PERP, SYNPO2 and the Wnt pathway may also contribute to BEEC etiology. This study provides the first expression profile of urogenital genes during bladder development and points to the highprobability candidate genes for BEEC.

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Clinical and molecular characterization of the bladder exstrophy‐epispadias complex: analysis of 232 families

Cited by 80 publications

References 32 publications

Epidemiological Survey of 214 Families With Bladder Exstrophy-Epispadias Complex

Epidemiological Survey of 214 Families With Bladder Exstrophy-Epispadias Complex

CNV Analysis in Monozygotic Twin Pairs Discordant for Urorectal Malformations

Genome-wide expression profiling of urinary bladder implicates desmosomal and cytoskeletal dysregulation in the bladder exstrophy-epispadias complex

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