Beckwith-Wiedemann syndrome (BWS)

Beckwith-Wiedemann syndrome (BWS) is a congenital (present at birth) overgrowth syndrome that occurs in approximately one in 15,000 births. This information from Great Ormond Street Hospital (GOSH) explains the causes, symptoms and treatment of BWS and where to get help.A syndrome is a collection of features often seen together. BWS is variable – some children have a number of features of the condition, others have only one or two. The condition is named after the two doctors who recognised and described it in the 1960s.

The most common features of the condition include:

• Increased height and weight at birth or in childhood.
• Asymmetry of growth, for example one arm or leg larger than the other (hemihypertrophy).
• Large tongue size (macroglossia).
• Low blood sugar in the first few days or weeks of life (neonatal hypoglycaemia).
• Umbilical hernia or other abdominal wall defect, for example exomphalos where the intestines and sometimes other organs such as the liver remain inside the umbilical cord but outside the abdomen at birth.
• Some children with the condition are at risk of Wilms' tumour of the kidney.

Other features of the condition include subtle alterations in the shape of the ears and, rarely, cleft palate or a congenital heart defect. Tumours other than Wilms' tumour, for example hepatoblastoma (childhood liver tumour), occasionally occur in childhood but are much less common. Learning difficulties are not part of the condition other than in the very small number of children with a complex chromosome abnormality.

The condition is diagnosed by a combination of assessment of clinical features and molecular testing. Testing is nowadays very straightforward and is usually carried out using a blood test. It is usually arranged by a paediatrician or clinical geneticist. In 80 per cent of children with the condition, the molecular testing is positive. Where testing is negative, a clinical geneticist will advise on whether they can confirm the diagnosis on clinical grounds alone.

BWS is caused by abnormalities at chromosome 11p15. There are a number of different abnormalities that we see. The names are quite complicated, but are important to the doctors so they can give you the right advice. Most of these cannot be inherited and have a very low chance of happening again in the family. These include:

• KvDMR hypomethylation (this is the cause of 50 per cent of children with BWS).
• Paternal uniparental disomy 11p15, often written UPD 11p15 (20 per cent).
• H19 hypermethylation (five per cent).

A few can be inherited and can have an increased chance of happening again in the family. These include:Approximately 20 per cent of children with BWS have no detectable molecular cause using current techniques. The cause in these children is not known. Your clinical geneticist will be able to explain the genetic test results to you and into which group your child falls.

• CDKN1C mutations (five per cent).
• Paternal 11p15 duplication, often as part of a chromosome translocation (one per cent).
• H19 microdeletion (less than one per cent).

The treatments and medical follow-up required depend on the clinical features of the child and the molecular results. All children should be seen by a clinical geneticist at initial diagnosis to advise on follow-up and the chance or recurrence of the condition in the family. Where there is a high risk of recurrence, the family will have the chance to ask about testing in pregnancy. Children will often have regular appointments with a general paediatrician during early childhood.

When they are first born, all children should have monitoring of their blood sugars before feeds for 48 hours. This may need to continue, for example if measurements are low. Children born with a major abdominal wall defect (exomphalos) will usually require surgery in the first few days of life. This will usually have been detected during pregnancy and the family aware of the need for surgery. Children with hemihypertrophy affecting the legs should be referred for assessment by an orthopaedic surgeon. In many cases, all that is required is a shoe orthotic such as a heel raise. Some children undergo minor surgery later in childhood to slow the growth of the longer leg.

Macroglossia may cause difficulties with feeding, speech, the development of the teeth and jaws, and increased drooling. A specialist speech and language therapist can provide support from infancy. Referral to a specialist team is often beneficial. There is a national specialised service for children who have macroglossia associated with BWS at GOSH. The aim of the service is to prevent or resolve the problems associated with macroglossia and to enable the best functional outcome. Some children may require tongue reduction surgery.

Some children with BWS are at increased risk of Wilms' tumour of the kidney. Wilms' tumour usually occurs in young children under the age of five years. It is very well treated and is cured in around 90 per cent of children. Wilms' tumour has never been reported in children with BWS caused by KvDMR hypomethylation. This is the commonest cause of BWS. Thousands of children with KvDMR hypomethylation have now been followed up and it is clear that they do not need Wilms' tumour surveillance.

For all other children with BWS, we recommend kidney ultrasound scans every three to four months until the age of seven years. Tumours other than Wilms' tumour are uncommon in BWS. As they are uncommon and because there are no reliable screening tools, we do not recommend specific surveillance other than for Wilms' tumour.

Children with BWS grow up to be healthy adults. Most do not need any specialist follow-up in adulthood. We recommend that adults with BWS ensure that they have had genetic testing to confirm their molecular subtype of the condition before they have children. This will allow them to receive the correct advice on the risk of the condition occurring in their children. The risk is low for most cases but is higher in some (see above). If they have not been tested or have not received recent advice, they should ask their family doctor (GP) to refer them to their local Clinical Genetics Service.