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Beckwith-

Wiedemann
Syndrome
BWS
What is Beckwith-Wiedemann Syndrome ?
 Beckwith-Wiedemann Syndrome (BWS) is a Like many such disorders, Beckwith-
congenital overgrowth syndrome, which can Wiedemann Syndrome can vary in
affect all systems of the body. It was first its effects from child to child i.e.
recognized in 1963-64 by Dr J. Bruce some children are relatively mildly
Beckwith, a pediatric pathologist in America
affected while others have a wider
and, independently, by Dr H.E. Wiedemann,
a German geneticist. Each had found a range of physical problems. There
similar set of congenital abnormalities in are, however, some characteristics
children, which could not be found in any that are common to most BWS
other disorders - in other words, a new children. Most problems can be
syndrome. helped or even solved provided that
 BWS occurs once in approximately every accurate diagnosis is made and
15,000 births. This figure may be an under- appropriate treatment started.
estimate because of mild cases not being Those children who survive infancy,
diagnosed. Cases have been reported in most the great majority, are usually
developed countries. In the great majority of healthy, with their growth and
cases it appears to be an isolated event with appearance gradually becoming
no known relatives, but there is some normal.
evidence that the condition can be inherited.
Causes
 BWS pathogenesis involves disrupted imprinting of one or more genes because
the sex of the transmitting parent determines the pattern and risk of
transmission in familial cases.
 Maternal transmission is associated with dramatically greater penetrance.
 Approximately 15% of patients with BWS cluster in families; the remainder are
sporadic.
 Three distinct breakpoint cluster regions (BWS chromosome regions
[BWSCRs]) encompass the maternally derived rearrangements associated with
BWS.
 Most patients with BWS demonstrate biallelic expression of IGF-2 in various
tissues. Some patients with BWS demonstrate elevated serum levels of IGF-2,
which may reflect leakage into the vasculature from tissues with elevated
production. Because 20% of patients with BWS have no identified genotypic
disorder, one should not conclude that somatic overgrowth in patients with
BWS must result from tissue IGF-2 overexpression. Several murine models
have provided tantalizing glimpses into potential pathophysiologies for the
diverse spectrum of BWS phenotypes.
 IGF-2 overexpression in transgenic mice induces dose-dependent
organomegaly, overgrowth, and macroglossia.
Pathophysiology
 Although the underlying causes of BWS remain unclear, approximately 80% of
patients demonstrate genotypic abnormalities of the distal region of
chromosome arm 11p. The BWS region of 11p was the first identified example
of imprinting in mammals (ie, the process whereby the 2 alleles of a gene are
expressed differentially). Authors have most often used the term imprinted to
refer to the expressed allele. For example, the maternal allele of band 11p15.5
is normally expressed, or imprinted. Some authors, however, designate the
silent allele as the imprinted gene. When reviewing the literature, a reader must
bear in mind this inconsistent and confusing nomenclature. Imprinting has
been associated with structural modifications of DNA near the gene, such as
methylation or lack of acetylation. Several 11p genes are imprinted, including
p57 (a cation-independent cyclase), IGF-2 (the gene for insulinlike growth
factor-2 [IGF-2]), the gene for insulin, and H19.
 H19 is particularly interesting because this gene is transcribed but not
translated. H19 messenger RNA (mRNA) appears critical for proper
imprinting of the nearby insulin and IGF-2 genes because deletion of H19 or
transposition from its usual position relative to IGF-2 disrupts normal
imprinting. Recent evidence reveals that H19 mRNA binds IGF-2 mRNA
binding protein, which may be one mechanism by which it affects IGF-2
production.
What are the main characteristics of
BWS?

 There are many characteristics that are


associated with BWS, but most children who are
affected have only a few of them. The most
commonly found are described below:
 PREMATURITY
BWS children are usually born prematurely but are larger and
heavier than one would expect, given the shorter length of
gestation.
 MACROSOMIA
Height and weight over the 95% centile
 NEVUS FLAMMEUS
Reddened skin on the forehead and eyelids. This usually fades in
the first few years.
 WILMS TUMOURS
Tumours of the kidney. Around 7.5% of BWS children will
develop Wilms Tumour. Because of the aggressiveness of these
tumours, abdominal ultrasound scans should take place every
three months up to the age of 7 or 8 years. A baseline MRI scan
may also be performed. The susceptibility to these tumours
diminishes and is not usually a problem after the age of 8.
Children with one side of the body bigger than the other or
enlarged kidneys appear to be more susceptible to Wilms tumour
than other
 MACROGLOSSIA
An enlarged tongue,
which may cause
breathing, feeding and
speaking difficulties, as
well as excessive
dribbling. It may
increase susceptibility to
respiratory problems
such as bronchitis or
excess mucus. It may
also result in the
protrusion of the lower
jaw.
EAR LOBE
CREASES
These are
sometimes
found in
conjunction
with
indentations
behind the
upper rim of
the ear.
 BWS children
ABDOMINAL WALL
DEFECTS
 These vary in severity. The
worst problem is an
omphalocele which allows
intestines and possibly other
organs to protrude externally
into a covering membrane.
Less serious is an umbilical
hernia and the least worse
case is undue weakness and
separation of the abdominal
muscles, which leads to a
pot-bellied appearance. Lax
abdominal musculature can
cause problems with
constipation.
 HEMIHYPERTROPHY
Overgrowth of one half of the body or of one limb
while the rest of the body grows at a normal rate.
 VISCEROMEGALY
Enlarged abdominal organs, usually the kidneys,
liver, spleen, adrenals and pancreas.
 HEPATOBLASTOMA
Liver tumours. The risk of these diminishes after
the age of 3 years. They can also be detected by
abdominal ultrasound but, as not all the liver can
be viewed, afp (alpha-feta-protein) levels in the
blood are also monitored 3 monthly.
 CARDIOMEGALY or STRUCTURAL
CARDIAC ABNORMALITIES
Enlarged heart or heart defects. These are relatively
uncommon and may resolve without treatment.
Diagnosis of BWS

 Currently diagnosis of BWS is made by clinical


evaluation and not by genetic testing. Diagnosis
is generally based upon the child showing two
out of the five major characteristics. These
major characteristics are: macroglossia;
unexplained hypoglycaemia in the first four
months; ear creases or pits; abdominal wall
defect (even a mild umbilical hernia); and
macrosomia at birth.
The Genetics of Beckwith
Wiedemann Syndrome (BWS)

 Introduction
Beckwith Wiedemann Syndrome (BWS) is an
overgrowth disorder caused by changes in the activity
of growth promoting and growth suppressing genes.
The genetics of BWS are complex, but the effects of
the genetic changes are to cause increased activity of
growth promoting genes or reduced activity of growth
suppressing genes.
Causes of BWS
 The region of chromosome 11 involved in BWS is contains many genes.
For simplicity we will concentrate on two genes that have been implicated
strongly in BWS:
 • A growth suppressing gene CDKN1C (active from the maternal
chromosome, and sometimes called p57KIP2).
 • A growth promoting gene Insulin-like Growth Factor II (IGF2 which is
active from the paternal chromosome).
 It can be predicted that genetic changes that result in reduced activity of
CDKN1C or increased activity of IGF2 (or both!) would cause overgrowth.
 The activity of both of CDKN1C and IGF2 is regulated by chemical
switches; CDKN1C is controlled by KvDMR1 and IGF2 is controlled by
H19 DMR. These switches are turned ON and OFF by undergoing a
process called methylation. CDKN1C and IGF2 will only be active if their
corresponding chemical switch is in its methylated form, and therefore
turned ON.
 Usually it is not known why errors in the KvDMR1 and H19 DMR1 have
occurred, but there is some evidence from the UK and the USA that in
vitro fertilization techniques (IVF, “test tube babies”) may increase the risk
of such errors.
 Most children born with BWS do not have any relatives with
BWS, and there are five known causes of BWS:
 IGF2 can be over-active because both chromosomes 11 have been
inherited from the father, this affects one fifth (20%) of patients with
BWS. This phenomenon is called paternal uniparental disomy (UPD).
These children will have increased IGF2 and reduced CDKN1C
expression (because IGF2 is expressed from the paternal chromosome
and CDKN1C is not).
 BWS is very occasionally caused by other chromosomal abnormalities.
These may be inherited from their parents or may be caused by a mistake
occurring in the foetus during pregnancy.
 Mistakes (mutations) in their copy of CDKN1C inherited from the
mother are found in roughly one in twenty (5%) children with BWS
(although mistakes in CDKN1C are found in one half of families with
several members with BWS).
 Reduced levels of CDKN1C due to incorrect methylation of KvDMR1
affects 40-50% of children with BWS (in some cases this can also
increase expression of IGF2).
 Increased levels of IGF2 due to incorrect methylation of H19 DMR1
occurs in 5-10% of children with BWS
The four most common
causes of BWS, and how
they cause overgrowth. The
pink line represents the
maternal chromosome 11
and the blue line represents
the paternal
chromosome 11. U
represents an unmethylated
switch (the red traffic light
shows that the gene is off).
M represents a methylated
switch (the green traffic light
shows that the gene is on).
How does the genetic cause of BWS correlate with
the symptoms of BWS?

 Both reduced CDKN1C activity and increased IGF2 activity can


cause symptoms of BWS, but there are subtle differences
according to the precise genetic cause. For example BWS
children with a mutation in CDKN1C or a reduction in
CDKN1C activity are more likely to have exomphalos than
children with uniparental disomy or H19 DMR methylation
change. Children with UPD are often born with one side of their
body larger than the other (hemihypertrophy). Children with
UPD, and those with a methylation error at the H19 DMR
switch, have been suggested to be at a higher risk of developing
a tumour than other children with BWS.
Testing for BWS

 Not all genetic tests for BWS are available – even on a


research basis! However NHS testing is
 available in Birmingham Genetics Centre for 3 tests:
 1. Chromosome analysis
 2. Testing for uniparental disomy
 3. Testing for methylation at the KvDMR1 switch
 If these tests are negative it does not disprove the
diagnosis of BWS, as there are other causes of
 BWS that will not have been tested for and other causes
that cannot yet be tested for!
An example of how a mistake in CDKN1C can be inherited.
The genetic causes of BWS
What is the treatment?
 HYPOGLYCAMIA
Usually responds well to treatment with hydrocortisone,
intravenous glucose and/or diet within 1 to 4 months.
 ABDOMINAL WALL DEFECTS
If an omphalocele is present, surgery will be required soon
after birth and an umbilical hernia may also sometimes need
correction. Constipation may require medication.
 WILMS TUMOUR
This will require surgery to remove the affected kidney and
possibly chemotherapy and radiotherapy.
 HEMIHYPERTROPHY
May require orthopaedic surgery.
 TONGUE REDUCTION SURGERY
Wilms tumour
 Detection
Wilms tumour may be suspected following an abdominal ultrasound scan.
 Diagnosis
The following tests may be carried out: blood tests, urine tests, chest x-rays, ultrasound
scans or MRI or CT scans, including scans of the chest to check for any spread of the
disease. This process is known as staging. Final diagnosis, however, depends on
obtaining a biopsy (tissue sample from the mass), and examining it under a microscope
in order to verify that it has the characteristics of a Wilm’s tumor.
 Treatment
All children with Wilms tumour will have surgery. Initially this may only be a biopsy to
confirm the diagnosis. Chemotherapy may then be given to shrink the tumour before
the kidney is removed (nephrectomy). Sometimes nephrectomy is performed first and
chemotherapy is given afterwards. During surgery, the surrounding lymph nodes, the
area around the kidneys, and the entire abdomen will also be examined. The next steps
of treatment depend on whether/where the cancer has spread. Samples of the tumor
are also examined under a microscope to determine particular characteristics of the
cells making up the tumor. Depending on the stage of the disease at diagnosis,
radiotherapy may be given to the side of the abdomen where the tumour was found.
Constipation
 Many children with BWS will suffer from constipation due to their weak
abdominal muscles. If not treated this can result in problems such as
megarectum and megacolon. This means that a large volume of stool is
required to produce the sensation of needing to open the bowels. When
the child does go it is usually very painful and can result in tearing and
bleeding. This may in turn cause the child to withhold their stools to
avoid pain, making the constipation worse.
 Treatment will initially involve softening and evacuation of the retained
stools, and maintenance therapy using laxatives and more gentle
stimulants.
 Some of the drugs used include lactulose,docusate, picosulphate and
senna.
 It is obviously important that you try and give your child a high-fibre
diet with adequate fluid intake. Excessive milk intake should be avoided
as this can cause constipation in toddlers.
Mortality/Morbidity
 Race
 No race predilection is observed.
 Sex
 No sex predilection is noted.
 Age
 BWS is a congenital disorder. Wilms tumor is the most common
cancer in children with BWS, occurring in about 5-7% of all
children with BWS. Most children develop Wilms tumor before
age 4 years; however, children with BWS can develop Wilms
tumor when they are as old as 7 or 8 years. By age 8 years, 95%
of all Wilms tumor cases have been diagnosed (DeBaun, 1998).
Conclusions

 Although the IGF2 and H19 genes are well characterized, the
downstream effectors of IGF2 have not been elucidated in
detail, and the function of H19 RNA is enigmatic. It is
reasonable to speculate that the link between the functions of
the IGF2 and CDKN1C gene products that are revealed by their
involvement in BWS might turn out to be the first of many
examples of functional interactions between genes within an
imprinted gene cluster. Thus, clustering of imprinted genes
enables coordinate regulation of imprinting across large domains
and more local mechanisms within specific regions of the
domain. Thus, on 11p15.5, BWSIC1 may provide a local
mechanism for regulating IGF2 and H19 imprinting, whereas a
second mechanism, possibly related to chromatin structure,
regulates imprinting over a larger distance.