Beckwith-Wiedemann Syndrome

What is Beckwith-Wiedemann Syndrome?

Beckwith-Wiedemann syndrome (BWS) is a common birth defect that causes excessive growth. It happens due to certain genetic and non-genetic changes affecting control of genes on chromosome 11p15.

BWS is most notably characterized by one side of the body growing more than the other (hemihypertrophy), large body size (macrosomia), big tongue (macroglossia), and issues with the abdominal wall. People with this syndrome are also more likely to develop cancers during childhood. But, given the variety of symptoms, diagnosing BWS can be tricky. Recognizing the condition early, ideally when a child is still in the womb or just after birth, is crucial for quick treatment and management of any resultant issues.

This syndrome is named after American pediatric pathologist John Bruce Beckwith and German pediatrician Hans-Rudolf Wiedemann. These doctors independently reported the symptoms of the condition in 1963 and 1964, respectively.

What Causes Beckwith-Wiedemann Syndrome?

Beckwith-Wiedemann syndrome is a complex condition that is mainly associated with an abnormality in chromosome 11p15.5. This abnormality impacts cell growth and development. The problem starts with a process called genetic imprinting, where only one copy of a gene gets activated, and this activation depends on whether the mother or father carried the gene.

Two specific areas, labeled IC1 and IC2, control gene expression in chromosome 11p15. A process called methylation, which turns genes off, usually occurs in the father’s gene at IC1 and the mother’s gene at IC2. However, in those with Beckwith-Wiedemann syndrome, we often see the following issues:

• The mother’s gene at IC2 loses its methylation in 50% to 60% of cases.
• Both copies of chromosome 11p15 come from the father in 20% to 25% of cases.
• The mother’s gene at IC1 becomes methylated in 5 to 10% of cases.
• Genetic mutations occur in 5% of individual cases and 40% of family cases.
• In less than 1% of cases, there are changes to the structure of the chromosomes.
• There’s an unknown issue in 10% to 15% of cases.

The variety of symptoms and the complicated genetic factors of Beckwith-Wiedemann syndrome make diagnosing the condition difficult. Genetic testing and molecular analyses are often used to confirm a diagnosis and identify specific genetic abnormalities. However, the exact cause of the syndrome is still unidentified in many cases.

Risk Factors and Frequency for Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann Syndrome (BWS) is a condition that is estimated to occur in about 1 in every 10,000 to 13,700 live births. However, it might be more common than this estimate suggests because cases with less obvious symptoms may not be diagnosed. People of all ethnic backgrounds can develop BWS and it affects both males and females equally. There is also a connection between BWS and assisted reproductive techniques (ART). In fact, ART can increase the chances of having BWS by ten times.

Signs and Symptoms of Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann Syndrome, or BWS, is a complex health condition that affects multiple systems in the body. The symptoms and health problems that come with BWS can be very different from one person to another, and can also change as a person gets older.

Pregnant women carrying a baby with BWS may have complications such as gestational hypertension, preeclampsia, gestational diabetes mellitus, vaginal bleeding, polyhydramnios, having a larger than normal baby (macrosomia), abnormally high levels of α-fetoprotein (AFP), and organ enlargement detected by ultrasound. At birth, the baby may be premature, have a larger than normal placenta (placentomegaly), or develop issues related to being too big, like cephalohematoma and brachial plexus injury. BWS can sometimes run in families.

In the newborn period, babies with BWS can face a host of issues like being larger than normal (macrosomia), different size of body parts (hemihyplasia), different size of limbs, distinctive facial features, and abdomen wall defects. In addition, their organs (like liver, kidneys, spleen, pancreas, thymus, heart, and adrenal glands) could be abnormally large. They may also suffer from kidney abnormalities and heart defects. Their facial features typically include enlarged tongue (macroglossia), noticeable eyes, facial lines below the eyes, underdeveloped mid face, forward jutting jaw, creases on the front part of the earlobe, indents at the back of the ear, and a birthmark on the forehead. Less common features are cleft palate, extra nipples, extra fingers or toes, and undescended testis. Newborns with BWS can also have low blood sugar due to too much insulin.

• Being larger than normal (macrosomia)
• Different size of body parts (hemihyplasia)
• Distinctive facial features
• Abnormalities in the abdominal wall
• Enlarged organs
• Kidney abnormalities and heart defects
• Abnormal facial features
• Less common features like cleft palate, extra nipples, extra fingers or toes, and undescended testis
• Low blood sugar count

As they grow into infancy, childhood, and adolescence, these facial features usually become less noticeable over time. The child’s height and weight often stay near the 90th percentile, while the head size tends to become closer to the average. Development is usually normal unless there is a specific genetic abnormality or complications during birth. Issues like kidney stone, kidney cysts, and repeated urinary tract infections may develop from infancy to adolescence. They are also at risk for certain types of cancers, so they need to be monitored regularly. The cancers more often seen are Wilms tumor and hepatoblastoma, but they can also get neuroblastoma, adrenocortical carcinoma, and rhabdomyosarcoma. The risk for getting cancer is about 5-10%, and most often occurs within the first 7 years of life.

As adults, their height is usually within the normal range. The difference in limb size can continue or worsen, leading to curvature of the spine (scoliosis). Male individuals may face fertility concerns due to problems with testing or undescended testes. There is not enough information on fertility for females with BWS. All individuals with BWS do not have every mentioned symptom and the severity and combination of symptoms can be different for each person.

Testing for Beckwith-Wiedemann Syndrome

Diagnosing Beckwith-Wiedemann Syndrome, commonly shortened to BWS, is primarily based on noticeable physical traits and medical symptoms (clinical criteria) and then confirmed through genetic testing. Because the condition can show up in many different ways in patients, there’s no unanimous agreement on diagnosis criteria within the medical community. Experts generally agree that a patient’s individual physical and health details should take precedence over set criteria. Moreover, even if genetic tests come back negative, it doesn’t necessarily mean that BWS isn’t present.

In regards to clinical diagnosis of BWS, a variety of criteria have been proposed over the years. Currently, it’s widely considered acceptable to make a clinical diagnosis based on a combination of major and minor symptoms. When patients exhibit three major symptoms, or two major and at least one minor symptom, it supports a diagnosis of BWS.

Major symptoms can include an umbilical hernia, an unusually large tongue, excessive newborn weight or growth, certain forms of tumors (like Wilms tumor), misshaped ears, enlarged organs, uneven growth of body parts, and abnormal kidneys. Also, a family history of BWS or a cleft palate can be major indicators of the condition.

Minor symptoms may include excess amniotic fluid during pregnancy, an enlarged placenta or umbilical cord, prematurity, low blood sugar in newborns, a birthmark on the forehead, unusual facial features, an enlarged heart or other heart issues, abdominal separation, extra fingers or toes, additional nipples, or advanced bone growth for their age.

More recently, a new diagnostic approach has been proposed by Brioude et al in 2018. They’ve offered a way to predict BWS by assigning points to key and suggestive features. Cardinal (key) features, such as an unusually large tongue, umbilical hernia, excessive growth on one side of the body, specific types of tumors, an overabundance of insulin, and certain signs in the adrenal glands or placenta. Suggestive features include unusually high birth weight, a facial birthmark, excessive amniotic fluid or an enlarged placenta during pregnancy, creases or pits in the ears, temporary low blood sugar, embryonic tumors, enlarged kidneys or liver, and an umbilical hernia or abdominal separation.

In this system, cardinal features are assigned two points while suggestive features earn one point. A total score of four or more confirms a BWS diagnosis without the need for additional testing. If the score comes in at two or three, genetic testing is recommended. A score lower than two doesn’t meet the criteria for further testing.

In terms of genetic testing for BWS, the use of molecular techniques is common due to the range of molecular abnormalities that can cause the condition. Even if a test comes back negative, it doesn’t necessarily rule out the disorder. Most often, testing is conducted on DNA from blood samples, but samples from cheek swabs, skin cells, or surgically removed tissue can also be used to improve detection accuracy.

Common techniques for testing include methylation analysis, sequencing analysis (gene-targeted sequencing), chromosomal microarray, SNP array, or microsatellite analysis, and karyotype or fluorescence in situ hybridization. The best choice of technique often depends on the available resources, the particular symptoms of the individual, and what genetic cause is suspected.

For unborn babies suspected of having BWS due to family history or clinical symptoms, genetic testing and counseling are recommended. The preferred prenatal diagnostic tests are methylation analysis and CDKN1C sequencing. If the prenatal tests suggest BWS, tests should be conducted after birth to confirm the diagnosis.

Treatment Options for Beckwith-Wiedemann Syndrome

When a diagnosis of BWS is made or suspected, it is crucial that a doctor creates a personalized plan for the patient due to the range of different symptoms that can occur.

Before Birth

If BWS is diagnosed or suspected during pregnancy, preparation needs to be made for potential complications, which can include complications for the mother, birth injuries related to a large baby, and low blood sugar after birth. Ideally, the baby should be delivered in a place that has a unit specialized in newborn intensive care.

After Birth: Low Blood Sugar

Newborns should be closely monitored for signs of low blood sugar in the first 2 days of life. If low blood sugar occurs it should be managed using standard guidelines. If no low blood sugar is detected after 2 days, a blood test for sugar, insulin, and ketones is recommended before leaving the hospital.

Growing Too Fast

Regular checks on growth are necessary, as BWS patients may grow too fast. Treatment options for this overgrowth can be considered. Measurements should be taken at least once a year to check for lopsided growth. If there is a noticeable difference in leg length, see a pediatric orthopedic surgeon. However, if the difference is in arm length, it can usually be just monitored unless it is causing severe functional problems.

Large Tongue

If feeding problems occur due to a large tongue, a feeding specialist and dietitian may be needed. If breathing problems are suspected, evaluations including sleep studies, lung consultations, and ear nose and throat consultations may be needed. The tongue may need to be surgically reduced if certain complications occur like feeding issues, ongoing drooling, speech problems or appearance-related social issues. Surgery, if needed, is usually done after 1 year of age, unless severe breathing issues require it earlier.

Abdominal Wall Defects

For patients who have defects of the abdominal wall, it is important to tailor the treatment to the specific circumstances of the patient. Surgery may be considered depending on the overall health of the patient, the size of the defect, and complications that may have arisen. Often, surgery is delayed until the child is stable and strong enough.

Heart Issues

Once BWS has been diagnosed, a basic heart check should be done. If abnormalities are suspected, a pediatric heart specialist may be needed. Further, follow-up checks and heart tracings are recommended yearly for patients with a certain genetic oddity.

Kidney Complications

When a diagnosis is made, checks for kidney irregularities should be done, as well as during the transition to adult healthcare. If any irregularities are found, consultations with kidney and urinary system specialists are necessary. Kidney stones and buildup of calcium in kidneys should be concurrently monitored with abdominal checks for tumors.

Tumors

BWS increases the risk of developing cancer, which is estimated to be between 5% and 10% in the first decade of life, with most cases occurring in the first 2 years. Various screening programs aim for early detection to reduce illness and improve survival chances.

In the United States, the tumor screening protocol includes an ultrasound and blood tests at the time of diagnosis, which then continues every 3 months until age 4, and every 3-4 months till age 7 or 8. The ultrasound is able to identify the most common tumors associated with BWS. However, the routine use of blood tests for monitoring is controversial because babies with BWS often have higher levels of these proteins in their blood, which makes interpretation challenging.

Although certain genetic defects have a higher risk for certain types of cancer, most hospitals use the same screening protocol for all BWS patients. Future management could benefit from genetic-guided tumor screening.

Brain Development

Usually, brain development is normal. However, monitoring by a pediatrician is advised, especially for patients with abnormal chromosomes or a history of complications around the time of birth, such as premature birth, birth trauma or neonatal hypoglycemia.

Long-Term Complications

A thorough health check-up is suggested when the patient turns 16-18 years old to catch any complications that adult healthcare services need to follow up on. Genetic counseling should be offered for future family planning. Continuous education and guidance are critical for individuals with BWS and their families.

Psychological Support

A care plan for BWS includes psychological services, specialist counseling, and family support. Encouraging their confidence and self-esteem is essential for individuals with BWS. Their strengths, achievements, and worth beyond their condition need to be highlighted to help enhance their self-perception. Families should be given information on BWS support groups right from the time of diagnosis.

What else can Beckwith-Wiedemann Syndrome be?

Overgrowth syndromes are conditions where some parts of the body grow more than they should. Some examples include:

• Isolated Hemihyperplasia
• Sotos Syndrome
• Simpson-Golabi-Behmel Syndrome
• Costello Syndrome
• Perlman Syndrome
• Weaver Syndrome
• NF1-Microdeletion Syndrome
• Proteus Syndrome

To confirm these syndromes, doctors will need to perform a thorough examination which may include checking the patient’s family history, physical symptoms, and running genetic or molecular tests if needed.

In some cases, these overgrowth syndromes may be mistaken for Isolated Hemihyperplasia. This is because they both often show similar changes in chromosome 11p15 and both may cause Hemihypertrophy, a condition where one side of the body grows more than the other.

There are also other conditions with symptoms that can be mistaken for overgrowth syndromes, such as:

• Trisomy 8 Mosaicism
• Congenital Hypothyroidism
• Mucopolysaccharidoses (for example, Hurler, Hunter, and Maroteaux–Lamy syndromes)
• Gangliosidoses
• Pompe Disease

If newborns have unusually large body size, a large tongue, and low blood sugar, doctors may need to rule out other possible causes like maternal diabetes. Also, in children suffering from delayed development but without any history of chromosomal abnormalities, premature birth, birthing trauma, or low blood sugar at birth, other reasons for developmental delays need to be considered.

What to expect with Beckwith-Wiedemann Syndrome

The outlook for Beckwith-Wiedemann Syndrome (BWS) can change based on several factors such as how serious the symptoms are, the specific type of BWS at the molecular level, when it was diagnosed, and whether or not BWS-related tumors have developed. Most people with BWS can expect to live a typical lifespan. As they grow into adulthood, their growth or facial differences might not be as noticeable.

Spotting BWS early, providing guidance on what to expect, regularly checking for tumors, and dealing with complications promptly can all help lead to better health outcomes.

Possible Complications When Diagnosed with Beckwith-Wiedemann Syndrome

In people suffering from Beckwith-Wiedemann Syndrome (BWS), a variety of complications can arise. These complications differ depending on the patient’s age and stage of life.

Some of the complications that can be faced by BWS patients include:

• During Pregnancy: Issues such as gestational hypertension, preeclampsia (high blood pressure during pregnancy), gestational diabetes, vaginal bleeding, excess amniotic fluid (polyhydramnios), premature birth, and complications related to an over-sized baby (macrosomia) such as brachial plexus injury and cephalohematoma (pooling of blood between the skull and skin of a newborn’s head).
• Newborn age: Being born prematurely, difficulties with breathing and feeding due to an enlarged tongue (macroglossia), low blood sugar (hypoglycemia), and in rare cases, heart muscle disease (cardiomyopathy).
• From Childhood to Adulthood: Continuation of speech or feeding difficulties due to macroglossia, development of cognitive impairment due to genetic or birth-related factors, development of specific types of tumors such as Wilms tumor and hepatoblastoma, kidney and urinary issues like nephrocalcinosis, nephrolithiasis, recurrent urinary tract infections, scoliosis due to unequal leg length, male fertility problems, and emotional coping challenges.

Identifying these complications early, vigilantly monitoring them, and intervening at the right time is essential to manage these complications and improve the health outcomes of individuals with BWS.

Preventing Beckwith-Wiedemann Syndrome

The best way to handle possible issues connected with BWS or Beckwith-Wiedemann Syndrome mostly involves spotting the issue early, routine checkups, and taking active steps to manage it. While it might not always be possible to avoid problems, there are certain steps that can help reduce risks and improve care for those with BWS:

* Regular doctor visits and check-ins
* Monitoring and screening for possible tumors
* Managing low blood sugar
* Early treatment for a larger-than-normal tongue
* Evaluations of the bones and muscles
* Mental health support

Patients and their loved ones should get counseling, education, help, and advice as soon as BWS is thought to be a possibility. Doctors can provide details for BWS support groups and resources like the National Organization for Rare Disorders (NORD) and the Beckwith-Wiedemann Children’s Foundation International. This all adds to a well-rounded approach to looking after patients.