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Cellular and molecular mechanisms in BWS Beckwith-Wiedemann syndrome Carolina Curto Ins G. Costa Rui Duarte Sandra Cr

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GENETIC BASIS Histone modification Non coding RNAs DNA methylation ICs (DMRs) Histone modification Non coding RNAs DNA methylation ICs (DMRs) Genomic Imprinting Fig1. Ilustrative image of chromossome 11p15.5. Source:http://www.intellmed.eu /cs/mdl/info/lsi-h-ras- orange/index.html Growth disorder associated with abnormalities in the imprinted domain of chromossome 11p15.5 Gene expression is altered according to the parental origin of the allele.

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GENETIC BASIS Chromossome 11p15.5 Histone modification Non coding RNAs DNA methylation ICs (DMRs) Histone modification Non coding RNAs DNA methylation ICs (DMRs) Genomic Imprinting Fig2. Ilustrative image of the mecanisms of DNA methylation.Source:http://cnx.org/content/m26565/1.1/

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GENETIC BASIS Maternal expressed genes: CDKN1C; KCNQ1; H19 Methylated IC2 and Non methylated IC1 Fig3. Schematic representation of chromossome 11p15.5 imprinted region on a normal individual. Source:Rosanna Weksberg,Cheryl Shuman and J. Beckwith: Practical Genetics- Beckwith- Wiedemann syndrome. European Journal of Human Genetics (2010);18,8-14. Fig4. Schematic representation revelent genes from chromossome 11p15.5.

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GENETIC BASIS Fig5. Schematic representation of chromossome 11p15.5 imprinted region altered. Source:Rosanna Weksberg,Cheryl Shuman and J. Beckwith: Practical Genetics- Beckwith-Wiedemann syndrome. European Journal of Human Genetics (2010);18,8-14.

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GENETIC BASIS Fig6. Distribution of BWS genetic causes.

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GENETIC BASIS (Segmental) Paternal Uniparental Disomy (Segmental) Mosaic Distribution Fig7. Schematic representation of Segmental Uniparental disomy mechanism. Source:http://www.peds.ufl.edu/divisions/genetics/teaching/syndrome_ge ne_maps.htm

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IC2 LOSS OF METHYLATION Imprinting control region 2 REGULATES CDKN1C gene hypomethylated Gene activity is reduced

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IC2 LOSS OF METHYLATION Cyclin-dependent kinase inhibitor 1C Responsible for restraining growth Cyclin-dependent kinases regulate the cell cycle. They must be binded to a cyclin in order to be active. CDKN1C binds to CDK and distorts cyclin binding CDKN1C acts as a tumor suppressor BWS Overgrowth and high risk of tumors

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IC1 GAIN OF METHYLATION Insulin-like growth factor 2 Promotes cell division before birth IC2 hypermethylation Increased activity of IGF2 gene Overgrowth and high risk of tumors (embryonal tumors)

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LOSS OF IMPRINTING Normally IGF2 Maternal copy Paternal copy INACTIVE ACTIVE LOI IGF2 Maternal copy Paternal copy ACTIVE Over-expression of IGF2 gene, which might stimulate the development of tumor cells

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SYMPTOMS Macrosomia Anterior linear ear lobe Creases/posterior helical ear pits Macroglossia Omphalocele/umbilical hernia Visceromegaly Embryonal tumors (Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma) in childhood Hemihyperplasia Cytomegaly of the fetal adrenal cortex (pathognomonic) Renal abnormalities including structural abnormalities, nephromegaly, nephrocalcinosis, later development of medullary sponge kidney Placental mesenchymal dysplasia Cardiomegaly Hypoglycemia Fig7. Illustrative pictures of symptoms related to this condition. Source:http://www.perinataljournal.com/20110193008;http://atl asgeneticsoncology.org/Kprones/HemihyperplasiaID10046.html;ht tp://www.pediatricsconsultant360.com/article/newborn- macroglossia-mass-umbilical-area-and-hypoglycemia

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DIAGNOSIS Blood analysis Abdominal X-Rays MRIs and Ecos Genetic Studies Clinical Evaluation Methylation sensitive MLPA Southern blotting Q-PCR determination of copy number GUSB Fig8. Different techniques used in BWS diagnosis. Source: Algar E, Dagar V, Sebaj M, Pachter N. An 11p15 imprinting center region 2 deletion in a family with Beckwith-Wiedemann syndrome provides insights into imprinting control at CDKN1C.PLoS One. 2011;6:e29034. doi: 10.1371/journal.pone.0029034.

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DIAGNOSIS Fig9. Schematic representation of the approches used to diagnose BWS. Source:Rosanna Weksberg,Cheryl Shuman and J. Beckwith: Practical Genetics- Beckwith-Wiedemann syndrome. European Journal of Human Genetics (2010);18,8-14.

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TREATMENT Standard supportive medical and surgical stratagies Dosing of -fetoprotein Tumor surveillance Prenatal diagnosis Fig10. Surgical treatment for macroglossia. Source:http://curiosoebizarroo.blogspot.pt/2010/08/macrogl ossia.html Fig11. CT scan image of bilateral Wilms Tumor. Source:http://med.brown.edu/pedisurg/Brown/IBImages/Abdomen /BilatWilms.html

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BIBLIOGRAPHY http://atlasgeneticsoncology.org/Kprones/HemihyperplasiaID10046.html http://cnx.org/content/m26565/1.1/ http://emedicine.medscape.com/article/919477-clinical#a0218 http://ghr.nlm.nih.gov http://med.brown.edu/pedisurg/Brown/IBImages/Abdomen/BilatWilms.html http://www.bv.fapesp.br/pt/bolsas/137779/investigacao-molecular-funcao-cdkn1c-p57kip2/ http://www.chc.min-saude.pt/servicos/Genetica/beckwith-wiedemann.htm http://www.intellmed.eu/cs/mdl/info/lsi-h-ras-orange/index.html http://www.ncbi.nlm.nih.gov/pubmed/15811927 http://www.pediatricsconsultant360.com/article/newborn-macroglossia-mass-umbilical-area-and- hypoglycemia http://www.peds.ufl.edu/divisions/genetics/teaching/syndrome_gene_maps.htm http://www.perinataljournal.com/20110193008 Rosanna Weksberg,Cheryl Shuman and J. Beckwith: Practical Genetics- Beckwith-Wiedemann syndrome. European Journal of Human Genetics (2010);18,8-14. Jacqueline R Engel, Alan Smallwood, Antonita Harper, Michael J Higgins, Mitsuo Oshimura,Wolf Reik, Paul N Schofield, Eamonn R Maher: Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome; J Med Genet 2000;37:921926 Shaffer LG, Agan N, Goldberg JD, Ledbetter DH, Longshore JW, Cassidy SB. American College of Medical Genetics statement of diagnostic testing for uniparental disomy. Available online. 2001. Accessed 6-26-12. Algar E, Dagar V, Sebaj M, Pachter N. An 11p15 imprinting center region 2 deletion in a family with Beckwith- Wiedemann syndrome provides insights into imprinting control at CDKN1C.PLoS One. 2011;6:e29034. doi: 10.1371/journal.pone.0029034.