A Case with Bladder Exstrophy and Unbalanced X Chromosome Rearrangement

Introduction Bladder exstrophy is a rare congenital malformation of the bladder and is believed to be a complex disorder with genetic and environmental background. We describe a young adult female with an isolated bladder exstrophy and with an X chromosome aberration. Patients and Methods Karyotyping identified an X chromosome rearrangement that was further characterized with array comparative genomic hybridization (CGH) and confirmed by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization (FISH) analysis. Results The identified X chromosome rearrangement in our index patient consists of a gain of chromosomal material in region Xq26.3-> qter and loss in region Xp22.12->pter. This aberration was also carried by her mother and sister, none with bladder exstrophy. All three have a disproportionate short stature, as expected due to the deletion of one of the copies of the SHOX gene on Xp22.3. X-inactivation studies revealed a complete skewed inactivation pattern in carriers. Crossover events in the maternal germline furthermore resulted in different genetic material on the rearranged X chromosome between the index patient and her sister. Conclusion Our findings suggest an X-linked genetic risk factor for bladder exstrophy

22q11.2 microduplication in two patients with bladder exstrophy and hearing impairment

Bladder exstrophy is a congenital malformation of the bladder and urethra. The genetic basis of this malformation is unknown however it is well known that chromosomal aberrations can lead to defects in organ development. A few bladder exstrophy patients have been described to carry chromosomal aberrations. Chromosomal rearrangements of 22q11.2 are implicated in several genomic disorders i.e. DiGeorge/velocardiofacial- and cat-eye syndrome. Deletions within this chromosomal region are relatively common while duplications of 22q11.2 are much less frequently observed. An increasing number of reports of microduplications of this region describe a highly variable phenotype. We have performed array-CGH analysis of 36 Swedish bladder exstrophy patients. The analysis revealed a similar and approximately 3 Mb duplication, consistent with the recently described 22q11.2 microduplication syndrome, in two unrelated cases with bladder exstrophy and hearing impairment. This finding was confirmed by multiplex ligation-dependent probe amplification (MLPA) and FISH analysis. Subsequent MLPA analysis of this chromosomal region in 33 bladder exstrophy patients did not reveal any deletion/duplication within this region. MLPA analysis of 171 anonymous control individuals revealed one individual carrying this microduplication. This is the first report of 22q11.2 microduplication associated with bladder exstrophy and hearing impairment. Furthermore the finding of one carrier among a cohort of normal controls further highlights the variable phenotype linked to this microduplication syndrome. (C) 2010 Elsevier Masson SAS. All rights reserved

The Swedish Reflux Trial in Children: I. Study Design and Study Population Characteristics

Purpose: We compared the rates of febrile urinary tract infection, kidney damage and reflux resolution in children with vesicoureteral reflux treated in 3 ways, including antibiotic prophylaxis, endoscopic therapy and surveillance with antibiotics only for symptomatic urinary tract infection. Materials and Methods: Children 1 to younger than 2 years with grade reflux were recruited into this prospective, open, randomized, controlled, multi-center study and followed for 2 years after randomization. The main study end points were recurrent febrile urinary tract infection, renal status on dimercaptosuccinic acid scintigraphy and reflux status. Outcomes were analyzed by the intent to treat principle. Results: During a 6-year period 128 girls and 75 boys entered the study. In 96% of cases reflux was detected after urinary tract infection. The randomization procedure was successful and resulted in 3 groups matched for relevant factors. Recruitment was slower than anticipated but after patients were entered adherence to the protocol was good. Of the children 93% were followed for the intended 2 years without a treatment arm change. All except 2 patients completed 2-year followup scintigraphy. Conclusions: Recruitment was difficult but a substantial number of children were entered and randomly assigned to 3 groups with similar basic characteristics. Good adherence to the protocol made it possible to address the central study questions

Classic Bladder Exstrophy: Frequent 22q11.21 Duplications and Definition of a 414 kb Phenocritical Region

Background: Classic bladder exstrophy (CBE) is the most common form of the bladder exstrophy and epispadias complex. Previously, we and others have identified four patients with a duplication of 22q11.21 among a total of 96 unrelated CBE patients. Methods: Here, we investigated whether this chromosomal aberration was commonly associated with CBE/bladder exstrophy and epispadias complex in an extended case-control sample. Multiplex ligation-dependent probe amplification and microarray-based analysis were used to identify 22q11.21 duplications in 244 unrelated bladder exstrophy and epispadias complex patients (including 217 CBE patients) and 665 healthy controls. Results: New duplications of variable size were identified in four CBE patients and one control. Pooling of our previous and present data (eight duplications in 313 CBE patients) yielded a combined odds ratio of 31.86 (95% confidence interval, 4.24-1407.97). Array-based sequence capture and high-throughput targeted re-sequencing established that all breakpoints resided within the low-copy repeats 22A to 22D. Comparison of the eight duplications revealed a 414 kb phenocritical region harboring 12 validated RefSeq genes. Characterization of these 12 candidate genes through whole-mount in situ hybridization of mouse embryos at embryonic day 9.5 suggested that CRKL, THAP7, and LZTR1 are CBE candidate genes. Conclusion: Our data suggest that duplication of 22q11.21 increases CBE risk and implicate a phenocritical region in disease formation. (C) 2014 Wiley Periodicals, Inc