Beckwith–Wiedemann syndrome (BWS)

Executive Summary

Beckwith Wiedemann syndrome (BWS) is the most common overgrowth and cancer predisposition disorder caused by the alteration in chromosome 11p15. Broader symptoms and physical findings have been represented, showing variations as per the disease severity in different children. Its characterization has increased the risk of childhood cancer-specific genetic characteristics. This disease does not have any established clinical diagnostic criteria. Some of the critical signs and symptoms of BWS include macrosomia, macroglossia, hemihyperplasia, umbilical hernia, renal abnormalities, cardiomyopathy, polyhydramnios and prematurity in the foetus, etc. BWS is diagnosed in a proband who has only one or two suggestive clinical signs. Children have symptoms of nevus flammeus, prominent occiput, midface hypoplasia, hemihypertrophy, genitourinary anomalies (enlarged kidneys), cardiac anomalies, musculoskeletal abnormalities, and hearing loss. The genetics of BWS involves the fact that almost >85% are sporadic, which means that no one else in the family is affected, and parents of an affected kid are not at a higher risk of having other children with BWS. The babies suffering from Beckwith Wiedemann syndrome (BWS) are reported with abdominal wall abnormalities that require surgical correction. The advances in treating newborn problems and premature infants have considerably reduced the real infant mortality rate related to BWS. An increased rate of ART conception is used for children with BWS. Almost one in every 13,700 children born in the United States are affected by Beckwith Wiedemann syndrome. Due to the great diversity in the syndrome’s presentation and the difficulty in diagnosing it, the actual incidence of BWS is unknown.

What is Beckwith Wiedemann syndrome (BWS)?

Beckwith Wiedemann syndrome (BWS) is a congenital overgrowth disorder characterized by an elevated risk of childhood cancer and specific genetic characteristics. It is usually present from birth. A small percentage of BWS cases (15%) are familial, indicating that a close relative may also have the disease, and parents of an affected kid may be more likely to have other children with BWS ^​1​. While children with BWS are at an elevated risk of childhood cancer, most children with BWS do not acquire cancer, and those who do can be successfully treated.

History

Dr John Bruce Beckwith, an American pathologist, and Dr Hans-Rudolf Wiedemann, a German paediatrician, reported a novel syndrome case in the 1960s. Known initially as EMG syndrome (for exomphalos, macroglossia, and gigantism), Beckwith Wiedemann syndrome or Wiedemann Beckwith syndrome evolved through time.

Dr Hans-Rudolf Wiedemann (born 16 February 1915 in Bremen, Germany, died 4 August 2006 in Kiel) coined the term exomphalos-macroglossia-gigantism (EMG) syndrome to describe a combination of congenital abdominal wall defects such as a hernia (exomphalos), large tongues (macroglossia), large bodies and long limbs (gigantism) (gigantism).

Presentation

Beckwith Wiedemann syndrome (BWS) has no established clinical diagnostic criteria. Individuals with one or more of the following primary and minor signs should be suspected of having Beckwith Wiedemann syndrome (BWS) ^​2​.

The most important findings related to BWS are given below:

• Macrosomia is a condition in which a person’s weight, length, and height are all over the 97th percentile.
• Macroglossia
• Hemihyperplasia is a type of hemihyperplasia (asymmetric overgrowth of one or more regions of the body)
• Umbilical hernia (also known as exomphalos) or omphalocele
• In children, the Wilms tumour, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma are examples of embryonal tumours.
• The liver, spleen, kidneys, adrenal glands, and pancreas are only a few intra-abdominal organs affected by visceromegaly.
• Adrenal cortex cytomegaly in the foetus (pathognomonic)
• Renal abnormalities include structural anomalies, nephromegaly, nephrocalcinosis, and a medullary sponge kidney development later in life.
• Linear wrinkles in the earlobes and helical ear pits at the back
• mesenchymal dysplasia of the placenta
• Cleft palate is a condition where the palate is separated from (rare in BWS)
• Cardiomyopathy is a condition in which the heart muscle becomes (rare in BWS)
• One family member with a clinical diagnosis of BWS or a history or symptoms suggestive of BWS)

Polyhydramnios and prematurity in foetuses with the condition are minor findings associated with BWS Pregnancy-related findings include polyhydramnios and prematurity in foetuses with the syndrome. Other findings include:

• Hypoglycemia in newborns
• Hemangiomas and nevus simplex (which often develop on the forehead, glabella, and back of the neck) are vascular lesions (cutaneous or extracutaneous)
• Midface retrusion and infraorbital wrinkles are standard facial features.
• Cardiomegaly or structural cardiac abnormalities
• Advanced bone age (typical in overgrowth and endocrine problems) Diastasis recti

Also Read: Symptoms based on Cancer types.

BWS is diagnosed in a proband who has one or more of the following symptoms ^​3​:

Three primary requirements are required, or two major criteria and at least one minor criterion. Note that BWS is a clinical spectrum, with some affected persons having only one or two suggestive clinical signs. As a result, the commonly accepted clinical criteria should be considered suggestions rather than absolutes. In other words, they can’t be used to rule out BWS and can’t be used to replace clinical judgement. In the presence of one or more clinical symptoms, an epigenetic or genomic change leading to aberrant methylation at 11p15.5 or a heterozygous BWS-causing pathogenic mutation in CDKN1C.

The majority of children with BWS do not have all of these characteristics. Other symptoms of BWS include nevus flammeus, prominent occiput, midface hypoplasia, hemihypertrophy, genitourinary anomalies (enlarged kidneys), cardiac anomalies, musculoskeletal abnormalities, and hearing loss in particular children. Furthermore, some premature neonates with BWS do not develop macroglossia until closer to their due date. Identifying BWS can be problematic due to the wide range of symptoms among people with BWS and the lack of a straightforward diagnostic test. DeBaun et al. attempted to standardize the classification of BWS ^​4​.

Neoplasms

Most children with Beckwith Wiedemann syndrome (BWS) do not acquire cancer. Still, they are 600 times more likely than other children to get certain pediatric cancers, such as Wilms’ tumor (nephroblastoma), pancreatoblastoma, and hepatoblastoma ^​5​. Individuals with BWS appear to be at a higher risk for cancer exclusively during childhood (particularly before the age of four) and do not appear to be at an increased risk for cancer in adulthood. If 100 children with BWS were followed from birth to ten years old, around ten instances would be predicted before the age of four, and about one case would be expected between the ages of four and ten.

They can typically be treated when Wilms tumor, hepatoblastoma, and mesoblastic nephroma are detected early. Early detection allows doctors to treat cancer while still in its early stages. In addition, the treatment is less harmful. Because early detection is so important, all children with BWS should be screened for malignancy. An abdominal ultrasound is done every three months until the child reaches the age of eight, and a blood test to assess alpha-fetoprotein (AFP) is done every six weeks until the child reaches the age of four. Based on their risk-benefit analysis, families and clinicians should decide on screening schedules for specific patients, including the age at which screening should be discontinued.

Genetics

The majority of Beckwith Wiedemann syndrome (BWS) cases (>85 per cent) are sporadic, which means that no one else in the family is affected, and parents of an affected kid are not at a higher risk of having other children with BWS. However, some (15%) cases of BWS are familial, meaning that a close cousin may also have the disease, and parents of an affected kid may be more likely to have other children with BWS. BWS has been demonstrated to be caused by mutations in a specific region of chromosome 11, known as 11p15.5, which results in overactivity of the IGF-2 gene (growth factor) and no active copy of CDKN1C. (inhibitor of cell proliferation gene).

A variety of genetic flaws can cause BWS. In different BWS patients, over five various 11p15.5 errors have been discovered. Maternal chromosomal rearrangements of 11p15.5 have been found in some cases ^​6​. Other patients have chromosome 11 paternal uniparental disomy (UPD), which means an additional paternal copy replaces the maternal copy. Many other patients have aberrant DNA methylation in various locations of 11p15.5, indicating that the region’s average epigenetic marks that govern imprinted genes have been changed. A few other patients have a single gene copy rather than two copies of 11p15.

The absence of a mutation in a kid with clinical signs and symptoms suggestive of BWS should not rule out a BWS diagnosis. Even after rigorous molecular testing, the same abnormality that causes BWS in a patient may remain unknown. Because clinicians cannot discover and test for all genetic causes of BWS, BWS remains a clinical rather than a genetic diagnosis. Because no standard diagnostic criteria have been independently verified with individuals with congenital or epigenetic abnormalities, the clinical diagnosis for BWS is limited. According to molecular investigations, only 7 of ten infants who met a study requirement for BWS exhibited genetic or epigenetic abnormalities. Because the genetics of BWS are complicated, a kid with BWS should be under the medical supervision of a geneticist or a BWS expert. IGF-2, CDKN1C, H19, and KCNQ1OT1 are among the genes implicated.

CDKN1C is associated with:

CDKN1C is a tumour suppressor gene that encodes a cyclin-dependent kinase inhibitor that functions as a negative regulator of cell growth. CDKN1C is also involved in foetal development, preventing the foetus from growing too big. Along with many other imprinted genes, it is found on the short arm of human chromosome 11 in the ICR2 area. Hypomethylation in the ICR2 area of the maternal allele can result in diseases such as cancer or a deficiency known as Beckwith-Wiedemann Syndrome because CDKN1C is preferentially produced in the mother ^​7​.

Management

In babies with Beckwith Wiedemann syndrome (BWS), abdominal wall abnormalities are prevalent and may require surgical correction. The most dangerous malformations are omphalocele, followed by an umbilical hernia and diastasis recti (least severe). An omphalocele is a congenital abnormality in which a newborn’s intestines and other abdominal organs protrude through the umbilicus and out of the belly. To avoid severe infection or shock, newborns with an omphalocele usually require surgery to return the abdominal contents to the abdomen ^​8​. A defect in which abdominal contents pass through a weak abdominal wall muscle at the umbilicus is known as an umbilical hernia.

The left and right sides of the rectus abdominis muscle, which are ordinarily connected, are separated by diastasis recti. Children with diastasis recti usually do not require therapy because the problem improves with age.

In roughly half of the children with BWS, neonatal hypoglycemia (low blood glucose in the first month of life) develops. Most hypoglycemia neonates are asymptomatic, and their blood glucose levels return to normal within days. Untreated, persistent hypoglycemia, on the other hand, might result in lifelong brain damage. Hypoglycemia in neonates with BWS is treated according to standard neonatal hypoglycemia guidelines. Children with BWS seldom (5% of the time) develop hypoglycemia following the newborn period and require more intense therapy. Tube feedings, oral hyperglycemic medications, or a partial pancreatectomy is necessary for such youngsters.

Macroglossia, or a large tongue, is a standard (>90%) and noticeable symptom of Beckwith Wiedemann syndrome (BWS). Infants with BWS and macroglossia can’t seal their mouth entirely in front of their vast tongue, which causes it to protrude. Macroglossia in BWS fades with maturity and usually does not require treatment, but it might pose problems for some BWS children. Macroglossia can cause breathing, eating, and speech problems in extreme situations. NHS England has commissioned the service as a highly specialised service, and it is based at Great Ormond Street Hospital.

A flat, crimson birthmark called Nevus flammeus (port-wine stain) is caused by a capillary (small blood vessel). Nevus flammeus on the forehead or back of the neck is common in children with BWS. Nevus flammeus is a benign skin condition that usually does not require treatment.

Hemihypertrophy (hemihyperplasia) is an asymmetry between the left and right sides of the body that occurs when one portion of the body grows faster than the other. Children with BWS with hemihypertrophy may have an isolated asymmetry of one body component or a hemihypertrophy that affects the entire side of the body. Isolated hemihypertrophy is linked to an increased risk of cancer. Children with BWS have cancers comparable in terms of type and age. As a result, children with hemihypertrophy should be screened for BWS using the standard cancer screening methodology. Hemihypertrophy can cause various orthopaedic issues, so an orthopaedic surgeon should be evaluated and follow by severe limb hemihyperplasia. Hemihyperplasia of the face can cause severe cosmetic problems, which a craniofacial team can help.

Prognosis The prognosis is excellent in general. Children with BWS normally do well and reach the expected heights depending on their parents’ heights. While children with BWS are at an elevated risk of childhood cancer, most children with BWS do not acquire cancer, and those who do can be successfully treated. Compared to their siblings, children with BWS did not have any significant delays. However, some children with BWS experience speech issues due to macroglossia or hearing loss.

In the last two decades, advances in treating newborn problems and premature infants have considerably reduced the real infant mortality rate related to BWS. No infant deaths were recorded in a survey of pregnancies that resulted in 304 infants with BWS. It compares to a 20 per cent fatality rate previously recorded. The data for the previous study came from a BWS registry, a database that may be slightly biased toward children who are still alive; nonetheless, death was not an exclusion factor for joining the registry. While infants with BWS are at a higher risk of infant mortality than the general population, the risk may not be as high as 20%.

Aspects of assisted reproduction technology

Assisted reproductive technology (ART) refers to methods that use artificial or partially artificial ways to achieve pregnancy. According to the CDC, ART methods entail surgically extracting eggs from a woman’s ovaries. In the lab, they are mixed with sperm. They can either be returned to the lady’s body or donated to another woman. The use of ART has been linked to epigenetic syndromes such as BWS and Angelman syndrome ^​9​. In children with BWS, three studies have found an increased rate of ART conception. In their in-vitro population, an Australian retrospective case-control research discovered 1 in 4000 risks of BWS, which is several times higher than the overall population. In the last two decades, advances in treating newborn problems and premature infants have considerably reduced the real infant mortality rate related to BWS. No infant deaths were recorded in a survey of pregnancies that resulted in 304 infants with BWS. It compares to a 20 per cent fatality rate previously recorded. The data for the previous study came from a BWS registry, which is a database that may be skewed toward live children.

Epidemiology

Beckwith Wiedemann syndrome affects one in every 13,700 children born in the United States; approximately 300 children with BWS are held each year. Because of the great diversity in the syndrome’s presentation and the difficulty in diagnosing it, the actual incidence of BWS is unknown. The number of infants born with BWS who have been recorded is likely low because many are born with BWS but have clinical characteristics that are less obvious and hence go unnoticed ^​10​. BWS has been observed in various ethnic groups, and it affects both men and women equally. Beckwith Wiedemann syndrome has a three to fourfold more significant risk in children conceived through in vitro fertilization.

References