Cellular and molecular mechanisms in BWS

Beckwith-Wiedemann syndrome

Carolina CurtoInês G. CostaRui DuarteSandra Cró

GENETIC BASIS

· 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.

GENETIC BASIS

Chromossome 11p15.5

· 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/

GENETIC BASIS

Maternal expressed genes:CDKN1C; KCNQ1; H19

Methylated IC2 and Non methylated IC1

Paternal expressed genes:IGF2 ; KCNQ10T

Methylated IC1 and Non methylated IC2

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.

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.

GENETIC BASIS

Paternal uniparental di-somy (20%)

IC1 gain of methylation (7%)

IC2 loss of methylation (50%)

CDKN1C mutations (10%)

Translocations/Inver-sions/Duplications (2%)

Unknown (11%)

Fig6. Distribution of BWS genetic causes.

GENETIC BASISPaternal

Uniparental Disomy

(Segmental)

Mosaic Distribution

Fig7. Schematic representation of Segmental Uniparental disomy mechanism. Source:http://www.peds.ufl.edu/divisions/genetics/teaching/syndrome_gene_maps.htm

IC2 LOSS OF METHYLATION

Imprinting control region 2

REGULATES

CDKN1C gene

hypomethylated

Gene activity is reduced

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

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)

LOSS OF IMPRINTING

Normally

IGF2Maternal copy

Paternal copy

INACTIVE ACTIVE

LOI

IGF2Maternal copy

Paternal copy

ACTIVE ACTIVE

Over-expression of IGF2 gene, which might stimulate the development of tumor cells

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://atlasgeneticsoncology.org/Kprones/HemihyperplasiaID10046.html;http://www.pediatricsconsultant360.com/article/newborn-macroglossia-mass-umbilical-area-and-hypoglycemia

DIAGNOSISBlood analysisAbdominal X-RaysMRIs and EcosGenetic Studies

Clinical Evaluation

Methylation sensitive

MLPA

Southern blotting

Q-PCR determination

of copy numberGUSB

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.

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.

TREATMENT

Standard supportive medical and surgical stratagiesDosing of α-fetoproteinTumor surveillance

Prenatal diagnosis

Fig10. Surgical treatment for macroglossia. Source:http://curiosoebizarroo.blogspot.pt/2010/08/macroglossia.html

Fig11. CT scan image of bilateral Wilms Tumor. Source:http://med.brown.edu/pedisurg/Brown/IBImages/Abdomen/BilatWilms.html

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