Cellular and molecular mechanisms in BWS

1. Carolina Curto Inês G. Costa Rui Duarte Sandra Cró Cellular and molecular mechanisms in BWS Beckwith-Wiedemannsyndrome

2. GENETIC BASIS Growthdisorderassociatedwithabnormalitiesin theimprinteddomainofchromossome 11p15.5 · Histonemodification · Non codingRNAs · DNA methylation ICs (DMRs) GenomicImprinting Fig1. Ilustrativeimageofchromossome11p15.5. Source:http://www.intellmed.eu/cs/mdl/info/lsi-h-ras-orange/index.html Gene expression is altered according to the parental origin of the allele.

3. GENETIC BASIS Chromossome 11p15.5 · Histonemodification · Non codingRNAs · DNA methylation ICs (DMRs) GenomicImprinting Fig2. Ilustrativeimageofthemecanismsof DNA methylation .Source:http://cnx.org/content/m26565/1.1/

4. GENETIC BASIS Fig3. Schematicrepresentationofchromossome 11p15.5 imprintedregionon a normal individual. Source:RosannaWeksberg,CherylShumanand J. Beckwith: PracticalGenetics- Beckwith-Wiedemannsyndrome. EuropeanJournalofHumanGenetics (2010);18,8-14. Maternalexpressed genes: CDKN1C; KCNQ1; H19 Methylated IC2 and Non methylated IC1 Paternal expressed genes: IGF2 ; KCNQ10T Methylated IC1 and Non methylated IC2 Fig4. Schematicrepresentationrevelent genes fromchromossome 11p15.5.

5. GENETIC BASIS Fig5. Schematicrepresentationofchromossome 11p15.5 imprintedregionaltered. Source:RosannaWeksberg,CherylShumanand J. Beckwith: PracticalGenetics- Beckwith-Wiedemannsyndrome. EuropeanJournalofHumanGenetics (2010);18,8-14.

6. GENETIC BASIS Fig6. DistributionofBWS genetic causes.

7. GENETIC BASIS Paternal UniparentalDisomy(Segmental) Mosaic Distribution Fig7. SchematicrepresentationofSegmentalUniparentaldisomymechanism. Source:http://www.peds.ufl.edu/divisions/genetics/teaching/syndrome_gene_maps.htm

8. IC2 LOSS OF METHYLATION Imprintingcontrolregion 2 hypomethylated REGULATES CDKN1C gene Gene activity is reduced

9. IC2 LOSS OF METHYLATION Cyclin-dependentkinaseinhibitor 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

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

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

12. SYMPTOMS • Macrosomia • Anterior linear ear lobe • Creases/posterior helical ear pits • Macroglossia • Omphalocele/umbilical hernia • Visceromegaly • Embryonaltumors (Wilmstumor, 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. Illustrativepicturesofsymptomsrelated to thiscondition. Source:http://www.perinataljournal.com/20110193008;http://atlasgeneticsoncology.org/Kprones/HemihyperplasiaID10046.html;http://www.pediatricsconsultant360.com/article/newborn-macroglossia-mass-umbilical-area-and-hypoglycemia

13. DIAGNOSIS ClinicalEvaluation Bloodanalysis Abdominal X-Rays MRIsand Ecos GeneticStudies Fig8. Differenttechniquesusedin BWS diagnosis. Source: AlgarE, 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.

14. DIAGNOSIS Fig9. Schematicrepresentationoftheapprochesused to diagnose BWS . Source:RosannaWeksberg,CherylShumanand J. Beckwith: PracticalGenetics- Beckwith-Wiedemannsyndrome. EuropeanJournalofHumanGenetics (2010);18,8-14.

15. TREATMENT Standard supportive medical andsurgicalstratagies Dosingof α-fetoprotein Tumor surveillance Prenataldiagnosis Fig10. Surgicaltreatment for macroglossia. Source:http://curiosoebizarroo.blogspot.pt/2010/08/macroglossia.html Fig11. CT scan imageofbilateral Wilms Tumor. Source:http://med.brown.edu/pedisurg/Brown/IBImages/Abdomen/BilatWilms.html

16. 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, MitsuoOshimura,WolfReik, Paul N Schofield, Eamonn R Maher: Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome; J Med Genet 2000;37:921–926 • Shaffer LG, Agan N, Goldberg JD, Ledbetter DH, Longshore JW, Cassidy SB. American College of Medical Genetics statement of diagnostic testing for uniparentaldisomy. 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.