Download PDF
Eur J Pediatr Surg 2014; 24(04): 353-359
DOI: 10.1055/s-0033-1349056
Case Gallery
Georg Thieme Verlag KG Stuttgart · New York

A Case with Bladder Exstrophy and Unbalanced X Chromosome Rearrangement

Cilla Soderhall
1   Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
2   Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
,
Johanna Lundin
3   Department of Women's and Children's Health, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
4   Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
,
Kristina Lagerstedt-Robinson
2   Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
4   Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
,
Giedre Grigelioniene
3   Department of Women's and Children's Health, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
4   Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
,
Goran Lackgren
5   Section of Urology, Uppsala Academic Children Hospital, Uppsala, Sweden
,
Christina Clementson Kockum
6   Department of Pediatric Surgery, University Hospital, Lund, Sweden
,
Agneta Nordenskjold
3   Department of Women's and Children's Health, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
7   Department of Pediatric Surgery, Astrid Lindgren Children Hospital, Karolinska University Hospital, Stockholm, Sweden
› Author Affiliations
Further Information

Publication History

01 November 2012

23 May 2013

Publication Date:
25 June 2013 (online)

Also available at
    Permissions and Reprints

Abstract

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.

Keywords

array-CGH - bladder exstrophy - MID1 - SHOX - X chromosome rearrangement
 

  • References

  • 1 ICBDMS. Epidemiology of bladder exstrophy and epispadias: a communication from the International Clearinghouse for Birth Defects Monitoring Systems. Teratology 1987; 36 (2) 221-227
    CrossrefPubMedGoogle Scholar
  • 2 Shapiro E, Lepor H, Jeffs RD. The inheritance of the exstrophy-epispadias complex. J Urol 1984; 132 (2) 308-310
    PubMedGoogle Scholar
  • 3 Gambhir L, Höller T, Müller M , et al. Epidemiological survey of 214 families with bladder exstrophy-epispadias complex. J Urol 2008; 179 (4) 1539-1543
    CrossrefPubMedGoogle Scholar
  • 4 Reutter H, Boyadjiev SA, Gambhir L , et al. Phenotype severity in the bladder exstrophy-epispadias complex: analysis of genetic and nongenetic contributing factors in 441 families from North America and Europe. J Pediatr 2011; 159 (5) 825-831 , e1
    CrossrefPubMedGoogle Scholar
  • 5 Nelson CP, Dunn RL, Wei JT. Contemporary epidemiology of bladder exstrophy in the United States. J Urol 2005; 173 (5) 1728-1731
    CrossrefPubMedGoogle Scholar
  • 6 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) 215-221
    CrossrefPubMedGoogle Scholar
  • 7 Reutter H, Qi L, Gearhart JP , et al. Concordance analyses of twins with bladder exstrophy-epispadias complex suggest genetic etiology. Am J Med Genet A 2007; 143A (22) 2751-2756
    CrossrefPubMedGoogle Scholar
  • 8 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 (3) 303-307
    CrossrefPubMedGoogle Scholar
  • 9 Boyadjiev SA, South ST, Radford CL , et al. A reciprocal translocation 46,XY,t(8;9)(p11.2;q13) in a bladder exstrophy patient disrupts CNTNAP3 and presents evidence of a pericentromeric duplication on chromosome 9. Genomics 2005; 85 (5) 622-629
    CrossrefPubMedGoogle Scholar
  • 10 Ludwig M, Utsch B, Reutter H. [Genetic and molecular biological aspects of the bladder exstrophy-epispadias complex (BEEC)]. Urologe A 2005; 44 (9) 1037-1038 , 1040–1044
    CrossrefPubMedGoogle Scholar
  • 11 Kosaki R, Fukuhara Y, Kosuga M , et al. OEIS complex with del(3)(q12.2q13.2). Am J Med Genet A 2005; 135 (2) 224-226
    PubMedGoogle Scholar
  • 12 Reutter H, Hoischen A, Ludwig M , et al. Genome-wide analysis for micro-aberrations in familial exstrophy of the bladder using array-based comparative genomic hybridization. BJU Int 2007; 100 (3) 646-650
    CrossrefPubMedGoogle Scholar
  • 13 Draaken M, Mughal SS, Pennimpede T , et al. Isolated bladder exstrophy associated with a de novo 0.9 Mb microduplication on chromosome 19p13.12. Birth Defects Res A Clin Mol Teratol 2013; 97 (3) 133-139
    CrossrefPubMedGoogle Scholar
  • 14 Zaki MS, Gillessen-Kaesbach G, Vater I , et al. Bladder exstrophy and extreme genital anomaly in a patient with pure terminal 1q deletion: expansion of phenotypic spectrum. Eur J Med Genet 2012; 55 (1) 43-48
    CrossrefPubMedGoogle Scholar
  • 15 Alkindi S, Battin M, Aftimos S, Purvis D. Focal Dermal Hypoplasia Due to a Novel Mutation in a Boy with Klinefelter Syndrome. Pediatr Dermatol 2012;
    PubMedGoogle Scholar
  • 16 Ludwig M, Rüschendorf F, Saar K , et al. Genome-wide linkage scan for bladder exstrophy-epispadias complex. Birth Defects Res A Clin Mol Teratol 2009; 85 (2) 174-178
    CrossrefPubMedGoogle Scholar
  • 17 Reutter H, Rüschendorf F, Mattheisen M , et al. Evidence for linkage of the bladder exstrophy-epispadias complex on chromosome 4q31.21-22 and 19q13.31-41 from a consanguineous Iranian family. Birth Defects Res A Clin Mol Teratol 2010; 88 (9) 757-761
    CrossrefPubMedGoogle Scholar
  • 18 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 (9) 1337-1343
    CrossrefPubMedGoogle Scholar
  • 19 Schoumans J, Johansson B, Corcoran M , et al. Characterisation of dic(9;20)(p11-13;q11) in childhood B-cell precursor acute lymphoblastic leukaemia by tiling resolution array-based comparative genomic hybridisation reveals clustered breakpoints at 9p13.2 and 20q11.2. Br J Haematol 2006; 135 (4) 492-499
    CrossrefPubMedGoogle Scholar
  • 20 Saal LH, Troein C, Vallon-Christersson J, Gruvberger S, Borg A, Peterson C. BioArray Software Environment (BASE): a platform for comprehensive management and analysis of microarray data. Genome Biol 2002; 3 (8) E0003
    PubMedGoogle Scholar
  • 21 Hupé P, Stransky N, Thiery JP, Radvanyi F, Barillot E. Analysis of array CGH data: from signal ratio to gain and loss of DNA regions. Bioinformatics 2004; 20 (18) 3413-3422
    CrossrefPubMedGoogle Scholar
  • 22 Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 1992; 51 (6) 1229-1239
    PubMedGoogle Scholar
  • 23 Wood HM, Babineau D, Gearhart JP. In vitro fertilization and the cloacal/bladder exstrophy-epispadias complex: a continuing association. J Pediatr Urol 2007; 3 (4) 305-310
    CrossrefPubMedGoogle Scholar
  • 24 Hipp J, Andersson KE, Kwon TG, Kwak EK, Yoo J, Atala A. Microarray analysis of exstrophic human bladder smooth muscle. BJU Int 2008; 101 (1) 100-105
    PubMedGoogle Scholar
  • 25 Rappold G, Blum WF, Shavrikova EP , et al. Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. J Med Genet 2007; 44 (5) 306-313
    CrossrefPubMedGoogle Scholar
  • 26 Jacobson Z, Glickstein J, Hensle T, Marion RW. Further delineation of the Opitz G/BBB syndrome: report of an infant with complex congenital heart disease and bladder exstrophy, and review of the literature. Am J Med Genet 1998; 78 (3) 294-299
    CrossrefPubMedGoogle Scholar
  • 27 Quaderi NA, Schweiger S, Gaudenz K , et al. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nat Genet 1997; 17 (3) 285-291
    CrossrefPubMedGoogle Scholar
  • 28 van den Berg IM, Laven JS, Stevens M , et al. X chromosome inactivation is initiated in human preimplantation embryos. Am J Hum Genet 2009; 84 (6) 771-779
    CrossrefPubMedGoogle Scholar
  • 29 Monkhorst K, Jonkers I, Rentmeester E, Grosveld F, Gribnau J. X inactivation counting and choice is a stochastic process: evidence for involvement of an X-linked activator. Cell 2008; 132 (3) 410-421
    CrossrefPubMedGoogle Scholar
  • 30 Bittel DC, Theodoro MF, Kibiryeva N, Fischer W, Talebizadeh Z, Butler MG. Comparison of X-chromosome inactivation patterns in multiple tissues from human females. J Med Genet 2008; 45 (5) 309-313
    CrossrefPubMedGoogle Scholar
  • 31 Amos-Landgraf JM, Cottle A, Plenge RM , et al. X chromosome-inactivation patterns of 1,005 phenotypically unaffected females. Am J Hum Genet 2006; 79 (3) 493-499
    CrossrefPubMedGoogle Scholar
  • 32 Sharp A, Robinson D, Jacobs P. Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet 2000; 107 (4) 343-349
    CrossrefPubMedGoogle Scholar
  • 33 Puck JM, Willard HF. X inactivation in females with X-linked disease. N Engl J Med 1998; 338 (5) 325-328
    CrossrefPubMedGoogle Scholar
  • 34 Orstavik KH. X chromosome inactivation in clinical practice. Hum Genet 2009; 126 (3) 363-373
    CrossrefPubMedGoogle Scholar
  • 35 Gerver WJ, De Bruin R. Relationship between height, sitting height and subischial leg length in Dutch children: presentation of normal values. Acta Paediatr 1995; 84 (5) 532-535
    CrossrefPubMedGoogle Scholar
  • 36 Karlberg P, Taranger J, Engström I , et al. I. physical growth from birth to 16 years and longitudinal outcome of the study during the same age period. Acta Paediatr Scand Suppl 1976; (258) 7-76
    PubMedGoogle Scholar