Caucasus International University Dr.Batuhan MİS Tbilisi/GEORGİA

1. Beckwith-Wiedemann
Syndrome
Dr.Batuhan Mis

2. What is Beckwith-Wiedemann Syndrome ?
• Beckwith-Wiedemann
syndrome (BWS) is an
overgrowth syndrome
associated with a
predisposition to embryonal
tumors
• most commonly Wilms‘
Tumor (WT).
• Overlapping clinical
phenotypes are seen in two
other disorders, Simpson-
Golabi-Behmel syndrome
(SGBS) and Perlman
syndrome (PS)

3. Beckwith-Wiedemann syndrome
• BWS is a genetically heterogeneous disorder
and most often associated with normal
chromosomes and a negative family history.
However, autosomal dominant transmission
of BWS is reported, as are chromosome
11p15.5 abnormalities.
• Uniparental paternal disomy (UPD) of
chromosome 11p15.5, and altered
expression of the imprinted gene insulin-like
growth factor 2 (IGF2) from the normally
repressed maternal allele

4. • Crucial to our understanding of the large variety of genetic
presentations in BWS is the concept of genomic imprinting, a process
in which gene expression specific to parent-of-origin is observed.
• The current genetic and molecular data for BWS are best explained
by a model assuming an imprinted domain for 11p15.5 whereby
altered expression of one or more genes in this region contributes to
the BWS phenotype.

5. • In this model, a defined chromatin structure is reflected in
coordinated control of multiple genes in the domain, as well as
specific patterns of replication timing and gene expression. Data
supporting this viewpoint include the maternally derived 11p15.5
translocation breakpoints associated with BWS, and the recent
finding that the normally asynchronous pattern of replication timing
for the imprinted gene IGF2 can be disrupted,
• shifted by a BWS-associated translocation 400 kh from IGF2. As we
unravel the molecular basis of the different BWS patient subgroups,
we will achieve a better understanding of this overgrowth syndrome
and its relationship to WT.

7. • A provisional diagnosis of BWS based on clinical assessment may be
confirmed by molecular/cytogenetic testing. Cytogenetically detectable
abnormalities involving chromosome 11p15 are found in 1% or fewer of
affected individuals.
• Molecular genetic testing can identify epigenetic and genomic altera
tions of chromosome 11p15 in individuals with BWS:
• Loss of methylation on the maternal chromosome at imprinting center 2
(IC2) in 50% of affected individuals;
• Paternal uniparental disomy for chromosome 11p15 in 20%; and
• Gain of methylation on the maternal chromosome at imprinting center 1
(IC1) in 5%. Methylation alterations associated with deletions or
duplications in this region have high heritability.

9. • Generally in sexual
reproduction, the organism bear
diploid number of
chromosomes i.e they
• contain two set of homologous
chromosomes. Out of these two
sets of chromosomes one
• inherited from the mother and
other from father.
• In some cases zygote is diploid
, but both chromosomes are
exceptionally inherited from
only
• one parent(from only mother
or father) is called uniparental
disomy (UPD).

10. • When the both chromosomes inherited from only mother called maternal UPD.
Mat UPD has
• been observed on 1,2,4,6,7,9,10,13-16,21-22, X chromosome. It is meiotic in
origin.
• When the both chromosomes inherited from only father called paternal UPD. Pat
UPD has
• been observed on 1,5-8,11,13-16 ,20-22, X and XY chromosome. It is mitotic in
origin.
• The most common mechanisms leading to UPD include chromosomal non
disjunction in the first
• or second meiotic division, but sometime errors in mitosis and somatic
recombination may also
• lead to UPD.

11. TYPES OF UNIPARENTAL DISOMY
• Heterodisomic UPD
• Isodisomic UPD

13. GENOMIC IMPRINTING
.
According to mendenlian inheritance presumes that maternal and paternal copies of a
gene are
equal function but this is however not case in genomic imprinting.
Genomic imprinting is a epigenetic process that leads to expression of an allele that is
inherited from one parent and the inactivation of its counterpart in the other parent.
When a chromosome is mutated or a deleted due to any causes (like UPD,
translocation ,
chromosomal rearrangement) inheritable gene is inherited from one parent that ensures
expression of this allele, no functional gene product is produced because the active
allele is mutated and the one from parent is silenced .

14. MECHANISMS OF UPD FORMATION
• Gamete complementation
• In gamete complementation,
• fertilization occurs between two
• aneuploid gametes, one nullisomic
• and the other disomic . The
disomic
• gamete contains a chromosome
pair
• resulting from nondisjunction in
• meiosis I or II.

15. Post fertilization error
• Postfertilization errors at early embryonic
• stages may also cause UPD, leading to UPD
• of the entire or only part of the
chromosome.
• Mitotic nondisjunction and subsequent
• duplication of the remaining chromosome
• leads to complete isodisomy . UPD for only
• part of a chromosome may arise from
somatic
• recombination or gene conversion, leading
to
• a minute UPD segment.

16. • UPD may lead to disorders by disrupting the balance of imprinted
genes or by reduction to
• homozygosity for a recessive disorder . UPD may, however, have no
effect on an individual
• when the maternal and paternal genomes are equivalent in terms of
and when no recessive
• disease alleles are transmitted . In the most extreme case, UPD may
be lethal.

17. Causes
In about one –fifth cases the cause is paternal UPD11 and
specifically the presence of two
copies of the 11p15.5 region instead of the usual one copy
from paternal and maternal
• Beckwith-Wiedemann syndrome(BWS) is related to chromosome
11p15.5 pat UPD.
• Symptomes
• Over growth of muscle,tongue,heart, kidney and liver.
• Larger adrenal cell and dysplasia are also seen.
• Children with BWS are at as incrased risk of developing several types
of cancer tumor
• particularly kidney cancer called wilms tumor.

18. Three genes are involve in BWS
IGF2, CDKN1, H19 genes

19. CDKN1 gene(cyclic dependent kinase inhibitor 1)
• CDKN1 gene is a tight binding
inhibitor of several C1cyclic /
cdk and a negative regulation of
cell proliferation.due to mat
UPD these gene mutated and
no proper functioning so cell
proliferation continous and
cause cancer
H19 genes
• These gene for non coding RNA
found in human.

20. H19 Gene and Igf2
• Two well-studied examples are the human H19 and insulin-like
growth factor 2 (Igf2) genes. These are located close to each other on
human chromosome 11. In a given cell, one copy of H19 (that on the
maternal chromosome) is expressed, whereas the other copy (on the
paternal chromosome) is switched off; for Igf2 the reverse is true—
the paternal copy is on and the maternal copy is off.

21. Complication
• Another 10 to 15 percent of people with Beckwith-Wiedemann
syndrome are part of
• families with more than one affected family member. In most of
these families, the
• condition appears to have an autosomal dominant pattern of
inheritance.

22. Treatment
• Patients with Beckwith-Wiedemann syndrome (BWS) may require frequent feedings
or
• diazoxide to treat their hypoglycemia.
• Octreotide or glucagon by subcutaneous infusion or injection is seldom necessary.
• The goal of therapy is maintenance of plasma glucose levels above 60 mg/dl at all
times.
• Infants and children must demonstrate the ability to maintain euglycemia during a
fast of age-
• appropriate duration. The normal duration of fasting for an infant or child depends
on body
• mass and the maturity of counter regulatory responses to hypoglycemia, which
include
• gluconeogenesis, glycogenolysis, and ketogenesis.

23. REFERENCES
• www.ncbi.nlm.nih.gov
• emedicine.medscape.com
• http://www.chop.edu