It is estimated that BWS occurs in one in 10,000 to 13,700 live births. However, it is likely that the actual number is higher than this as the milder forms of the disorder may not be diagnosed. It affects both sexes and individuals from all ethnicities equally. Assisted reproductive techniques such as in vitro fertilization (IVF) increase the risk of BWS. In the majority of the cases (about 85%) BWS is not inherited (sporadic) but it can also be inherited in about 15% of the cases.

The cause of BWS is complex and can involve both genetic and epigenetic changes to a region of chromosome 11 referred to as 11p15. Human genes are made of DNA molecules arranged into structures called chromosomes. Every person has 23 pairs of chromosomes, and therefore, two copies of each gene, one inherited from the mother (maternal copy) and one inherited from the father (paternal copy). 

Genes act as recipes that tell the body how to make certain products like proteins and how to function. Errors in these recipes can lead to dysfunctional or nonfunctional products. While genetic changes are changes to the DNA sequence of a gene itself (like spelling mistakes in the recipe), epigenetic changes are chemical modifications of the DNA molecule that regulate how these genes are turned on or off. The recipe itself remains unchanged, but these modifications regulate whether your body reads or skips over a recipe. This is known as gene expression. A gene that is turned off by epigenetic mechanisms is not expressed while a gene that is turned on is expressed. One of the major epigenetic mechanisms affecting the expression of genes is called DNA methylation. Adding methyl molecules to a gene turns it off. For more information about this, please refer to our tutorial on genetic inheritance. 

Generally, both the maternal and the paternal copies of each gene are expressed and active, however, imprinted genes are an exception to this. Genetic imprinting is a process whereby epigenetic changes turn off either the maternal or the paternal copy (depending on the gene) such that only one copy of the gene is expressed. These epigenetic changes occur during sperm and egg production and persist after conception throughout an individual’s life. These imprinted genes are grouped in clusters on the chromosome and the activity of each cluster is controlled by a nearby region on the chromosome called an imprinting control center (IC). 

In the case of BWS, the imprinted region on chromosome 11 contains genes that are normally under strict control of these epigenetic marks. Several of these genes are involved in regulating growth or act as tumor suppressors. The epigenetic markers in these regions are controlled by two main imprinting control centers that are involved in BWS. One region is controlled by imprinting center 1 (IC1) which is marked by epigenetic mechanisms (methylated) only on the paternal copy. The other one is IC2 which is marked by epigenetic mechanisms only on the maternal copy. The loss of the correct pattern of epigenetic markers in this region de-regulates the activity levels of the genes in the region which are normally tightly controlled. This can lead to BWS. Three important genes in this region that are involved in BWS are below: 

H19: This gene is normally active only on the maternal chromosome. It produces a molecule that seems to play a role in controlling cell growth and development.

IGF2 (Insulin-like Growth Factor 2): This gene is usually active only on the paternal chromosome. It's involved in promoting cell growth and development.

CDKN1C (cyclin-dependent kinase inhibitor 1C): This gene produces a protein that acts as a brake to the cell cycle, and therefore, regulates growth. It also prevents the uncontrolled division of the cells, and as such, acts as a tumor suppressor.

In BWS, some individuals show a disruption in the normal imprinting pattern of the ICR1 region. For example, the epigenetic marks on ICR1 may be abnormally increased on the maternal chromosome. As a result, the maternal copy of the H19 gene might not be as active as it should be, and the IGF2 gene might be more active than normal. Another epigenetic change that can cause BWS involves having decreased epigenetic markers on the maternal copy of IC2. This also causes a dysregulation of the genes in this region. 

In addition to epigenetic changes, molecular changes (spelling mistakes in the recipe) to the DNA of the maternally inherited CDKN1C gene itself can also cause BWS. As mentioned earlier, the protein product of the CDKN1C gene acts as a brake to the cell cycle. Genetic alterations in the CDKN1C gene are like errors in the recipe itself that can change the final product. This can result in decreased effectiveness of this brake, leading to uncontrolled cell growth and ultimately overgrowth and tumor predisposition. Mutations in this gene are autosomal dominant which means having one defective copy (maternal copy in the case of BWS) is sufficient to cause BWS.

Another mechanism is known as paternal uniparental disomy (UPD) of 11p15. This occurs when both copies of the 11p15 chromosome are from the father instead of one copy from the father and one copy from the mother. This occurs due to an error in cell division in early fetal development. In the case of BWS, this error is usually replicated in only a fraction of the cells, a state known as mosaicism. This means that some of the cells in the body of an affected individual may have UDP and some may have normal genetic content. UPD can have deleterious effects when the chromosome has imprinted regions as is the case with chromosome 11. If both copies of the chromosome are inherited from one parent (in BWS they are both from the father), the normal imprinting pattern in the region can be disrupted. This means that genes that are supposed to be active might be silenced, or genes that are supposed to be silenced might become active.

Structural changes to the chromosome itself such as duplications or deletions of the 11p15 chromosomal region can also cause BWS. 

In about 10-20% of the cases, no genetic or epigenetic cause can be identified. This is in part due to mosaicism in some of the involved mechanisms such as uniparental disomy. Since only a fraction of the cells are affected by UPD, the cells that are used for genetic and epigenetic testing may be completely normal while UPD exists in other cells that were not tested.

Below is a summary of the genetic and epigenetic causes of BWS:

• Loss of epigenetics markers (methylation) at IC2 on the chromosome inherited from the mother which dysregulates the expression of genes in this region such as CDKN1C (50-60% of the cases)

• Having two copies of the paternal 11p15 region of chromosome 11 (paternal UPD) instead of one maternal and one paternal copy (20-25% of the cases)

• Gain of epigenetic markers (methylation) at IC1 on the chromosome inherited from the mother which dysregulates the expression of genes such as IGF2 and H19 (5-10% of the cases)

• Autosomal dominant mutations in the CDKN1C gene inherited from the mother (5% of non-inherited and 40% of inherited cases) 

• Chromosomal rearrangements such as duplications and deletions involving chromosome 11p15 (less than 1% of the cases)

• No known genetic or epigenetic change (10-15% of the cases)

BWS is not inherited in the majority of individuals. If the underlying cause is an epigenetic change, BWS is likely not inherited and the risk of recurrence in future generations or in the individual’s siblings is low. A minority of individuals who have genetic changes can inherit BWS from their parents or pass it on to their children. 40% of the inherited cases are due to maternally inherited DNA changes in the CDKN1C gene. In such cases, if the affected individual is female, there is a 50% chance that they will pass on this disorder to their children, but if the individual is male, they will not pass it on as CDKN1C genetic mutations only cause BWS when inherited from the mother. Deletions or duplications of chromosome 11p15 can also increase the risk of recurrence in both the children and the siblings of the affected individuals. 

BWS is a complex disorder that affects multiple systems in the body. The symptoms depend on multiple factors including age and the specific genetic or epigenetic cause. 

During pregnancy: Mothers of affected babies may have complications such as gestational (pregnancy-related) diabetes, pregnancy-related high blood pressure, pre-eclampsia (high blood pressure, kidney damage and other organ damage), and vaginal bleeding. There may also be increased fluid around the fetus (polyhydramnios) and the fetus may be large (macrosomia), born prematurely (before 37 weeks), and show evidence of organ enlargement on sonography. 

Growth: Affected individuals may experience general overgrowth in height and/or weight. This overgrowth may start during pregnancy (macrosomia) which can be detected by ultrasound or after birth. While there is rapid overgrowth in childhood until 7-8 years of age, adult height tends to be within the normal range, although often on the higher end. In addition to generalized overgrowth, some children show one-sided overgrowth (i.e. one side of the body is larger than the other) leading to asymmetry. This is known as hemihyperplasia and is often evident at birth and can become less or more noticeable over time. This overgrowth is usually in the muscles but bone overgrowth can also occur. One-sided growth can lead to limb length discrepancy when one leg or arm is longer than the other. While adult height is often normal, limb length discrepancy may persist into adulthood and lead to abnormal curvature of the spine (scoliosis) if the legs are affected. Additionally, there may be enlargement of individual organs. Having a large tongue (macroglossia) is the most common feature in BWS, seen in 90% of affected individuals. There may also be an enlarged liver, kidneys, or spleen. BWS usually does not affect the head size. 

Embryonal Tumors: As a fetus develops during pregnancy, immature and primitive cells called embryonal cells develop into mature cells that form different organs such as the liver, kidneys, etc. Embryonal tumors are a group of childhood tumors that arise from these embryonal cells. BWS is associated with an increased risk of developing certain embryonal tumors. This is often the most concerning feature of BWS which prompts regular surveillance for early detection and treatment if such tumors arise. The most common tumors seen in BWS are Wilms tumor and hepatoblastoma. 

Wilms tumor, also known as nephroblastoma, is the most common kidney tumor in children. Often there are no symptoms or the only symptom may be one-sided abdominal swelling or mass that can be felt. Other symptoms that may be present include blood in the urine, frequent infections of the bladder and/or kidneys, and abdominal pain. In BWS, the highest risk of developing Wilms tumor is in the first seven years of life.

Hepatoblastoma is a type of tumor of the liver. They may be initially completely asymptomatic or can present as a mass on the right side of the abdomen that may grow rapidly over time. This mass may be mildly painful. Other symptoms may include inadequate growth (height and/or weight) and loss of appetite. This risk of developing hepatoblastoma is the highest in the first three to four years of life.

Other embryonal tumors that are seen less frequently in BWS are neuroblastoma (tumors arising from immature nerve cells), rhabdomyosarcoma (tumor of the muscles and/or bones), and adrenocortical carcinoma (tumor of the outer layer of the adrenal glands which sit on top of the kidneys and are responsible for the production of important hormones). 

The risk of developing an embryonal tumor depends on the exact genetic or epigenetic mechanism underlying BWS in each affected individual. The highest risk of tumor development is seen in individuals in whom BWS is due to the gain of epigenetic markers at IC1 on the chromosome inherited from the mother. Approximately one in 4-5 individuals develop a childhood tumor in this group, with almost all of those being Wilms tumor. The second highest risk is in individuals with uniparental disomy; approximately, one in six individuals develop a tumor in this group, with half of them being Wilms tumor. The lowest risk is in individuals with loss of epigenetic markers at IC2 on the chromosome inherited from the mother. It is estimated that 2-3% of these individuals develop a tumor. Additionally, children with BWS with no detectable genetic or epigenetic cause also have an increased risk for tumor development.

Low Blood Sugar: About half of affected babies experience low blood sugar levels shortly after birth (neonatal hypoglycemia). If severe and untreated, this can have significant effects on the future development of the baby. However, most cases are mild and resolve within a few days. If low blood sugars persist and are difficult to control, it may be due to increased insulin levels. Insulin is the hormone that promotes the uptake of sugar from blood by body cells, therefore reducing sugar levels in the blood. Individuals with BWS are at risk of having too much insulin as there may be overgrowth of the cells that produce insulin in a gland called the pancreas. 

Abdominal Wall Defects: Abdominal wall defects are among the common features in BWS. These are areas of weakness in the muscle or other layers of the abdomen that lead to problems such as omphalocele or umbilical hernia. An omphalocele is a defect where abdominal contents such as the bowels protrude out through a hole in the belly button area and can be seen outside the body covered with a thin and transparent layer. An umbilical hernia occurs when the abdominal contents such as the bowels protrude through a hole in the abdominal wall. It is seen as a bump in the belly button area that may get bigger when the baby cries or strains to pass stool. It is different from an omphalocele as an umbilical hernia is still covered by skin. Abdominal wall defects can be seen in about half of affected individuals.

Facial Features: Individuals with BWS may have characteristic physical features. As mentioned earlier, a large tongue is the most common feature seen in BWS and it can sometimes interfere with feeding or obstruct breathing in infants. Another common physical finding in BWS is small indentations at the back on the outer edge of one or both ears or creases on the soft part of the ear lobes. They may also have prominent creases below their eyes, thin upper lips, and a prominent jaw. The characteristic facial features often become less prominent as the child grows and are lost in later childhood.

Kidney Abnormalities: In addition to Wilms tumor, BWS is also associated with other kidney abnormalities, usually in the structure of the kidneys. These include enlarged kidneys, swelling and stretching of the kidneys due to urine accumulation (hydronephrosis), and renal medullary dysplasia where multiple small cysts form in the kidney tubules that collect urine. These may increase the risk of bladder and/or kidney infection and kidney stones and may affect kidney function over time.

Heart Abnormalities: Heart-related problems have also been seen in individuals affected by BWS, however, the association is not well-established. These can include an enlarged heart (cardiomegaly) which tends to resolve without treatment. In rare cases, there may be dysfunction of the heart muscle leading to symptoms such as sweating and difficulty feeding in newborns and infants, inadequate growth in weight gain in both infants and children, and shortness of breath with activity or lying down, cough, and ankle and leg swelling in adults. 

Others: Development is usually not affected and individuals have normal intelligence unless there is a history of severe low blood sugars in infancy or structural chromosomal changes in the 11p15 regions or brain malformations. In adulthood, infertility issues in males have been reported but they are not very common. 

Diagnosis of BWS is suspected based on the associated clinical features. Major features that should raise suspicion for BWS include abdominal wall defects such as omphalocele or umbilical hernia, a large tongue, high birth weight, and early overgrowth which may be generalized or one-sided, low blood sugar levels shortly after birth, the specific physical and facial features seen in BWS, organ enlargement (such as enlarged liver, spleen, or kidneys). In individuals with subtle features of BWS, developing an embryonal tumor may be the first feature that prompts investigation for BWS. Additionally, having a known family history of BWS is considered. If BWS is suspected based on these factors, molecular/genetic testing is done to confirm the diagnosis.

During pregnancy, certain features may be seen on ultrasound such as increased weight of the fetus, increased fluid around the baby, and structural abnormalities such as a large tongue, kidney changes, or omphaloceles. These features or family history of BWS or having had a previous child with BWS may prompt further investigations to assess the DNA of the fetus and diagnose BWS before birth.

Molecular tests are the main method of confirming the diagnosis of BWS. Given the complex and different molecular causes of BWS, diagnosis may require multiple steps. Molecular testing is often done using a blood sample. There are multiple tests that aid in the diagnosis of BWS, each one looking for a particular genetic or epigenetic cause of BWS.

Methylation analysis: Methylation is the process of adding epigenetic markers (methyl molecules) to certain areas of the DNA. As discussed earlier, BWS is commonly caused by increased or decreased epigenetic markers in certain areas of chromosome 11 (IC1 and IC2). Methylation analysis involves looking at the specific epigenetic markers on DNA. If one of the epigenetic patterns associated with BWS is identified on methylation analysis in the context of clinical features, that confirms the diagnosis of BWS.

Genetic sequencing: Genetic sequencing involves looking at the order of the four genetic building blocks that make up DNA (like checking each letter in a recipe). Mutations (spelling mistakes) in the CDKN1C gene or other genes related to BWS that are shown to be disease-causing can confirm the diagnosis of BWS. 

Microarray: A microarray is a test that checks the overall structure of the chromosome (checking the chapters in a cookbook as opposed to checking each letter). This test can identify chromosomal changes such as deletions or duplications in 11p15. 

It is important to note that negative genetic testing does not rule out BWS as up to 20% of affected individuals have negative genetic testing. This may be due to limitations in genetic testing or due to the presence of genetic or epigenetic changes causing BWS in a subset of cells in an affected individual or mosaicism. 

During pregnancy, if there are features associated with BWS on ultrasound or family history of BWS, further testing can be done to confirm the diagnosis prior to birth. These tests involve amniocentesis or chorionic villi sampling.

In amniocentesis, a long, thin, hollow needle is inserted through the skin into the uterus under the guidance of ultrasound to collect a sample of amniotic fluid. Amniotic fluid is the fluid that surrounds the fetus during pregnancy. The amniotic fluid contains cells shed by the fetus, and therefore, allows for genetic testing on fetal DNA. 

In chorionic villi sampling a small sample is taken from a layer of the placenta called chorionic villi which contains the same genetic material as the fetus. Depending on the location of the placenta, chorionic villi sampling can be done with a needle through the abdominal skin into the uterus similar to amniocentesis, or it may be done using a thin, hollow tube passed through the cervix via the vagina into the uterus. Because chorionic villi contain the same genetic material as the fetus, genetic testing results on these cells reflect the genetic content of the baby. 

The choice of amniocentesis versus chorionic villi sampling depends on a number of factors including the timing of pregnancy as each of these tests can be done during a particular window of time during pregnancy. Each of these tests is also associated with certain risks and complications which can impact the decision. Importantly, both these tests can be used for genetic testing (i.e. looking for spelling mistakes or changes in the structure of the DNA). However, only amniocentesis can be used for methylation analysis. Therefore, in the absence of a family history of BWS and a known genetic cause that can be detected on genetic testing without the need for methylation analysis, amniocentesis can provide more comprehensive answers. 

The management of BWS involves treatment of the specific features present in an individual and surveillance for all those affected. This requires a multidisciplinary team with different medical specialists.

If BWS is diagnosed in a baby during pregnancy, potential complications may be anticipated and planned for. For instance, parents may be suggested to deliver the baby in a hospital with a neonatal intensive care unit, in case complications occur and the baby requires more extensive medical treatment. Additionally, given the risk of low blood sugar after birth, blood sugar levels are monitored in the first couple of days of life. Low blood sugar levels are treated to prevent damage to the brain. Mild low blood sugar levels can be treated by frequent feeds or may require IV sugar supplementation if more severe. A specialist (endocrinologist) assessment may be needed if blood sugars are severely low, or persistent despite treatment. 

In some affected children, the tongue may be large enough to interfere with breathing, feeding, or speech. Treatment can involve special dietary modifications suggested by a dietician to make feeding easier or using specialized feeding aids. More severe feeding difficulties may require feeding tubes. A speech therapist can help with speech difficulties related to the size of the tongue. If the feeding challenges, breathing disturbances, or speech issues are severe, surgery may be needed to reduce the size of the tongue. 

Abdominal wall defects, particularly omphaloceles, may require surgery soon after birth to correct the deformity.

In terms of growth, management usually involves regular monitoring of growth and if one leg becomes longer than the other, the child may need to be seen by an orthopedic surgeon to discuss treatment options. Treatment may involve using a shoe lift to correct the discrepancy or surgery may be suggested depending on the severity of the discrepancy. If the length discrepancy is in the arms, no surgery is usually required.

One of the most important aspects of BWS management is surveillance for embryonal tumors. How the surveillance is carried out depends on the country and its specific guidelines. However, it generally consists of regular blood work and imaging at regular intervals. Blood work tests for the levels of a substance called alpha-fetoprotein (AFP) in the blood. This substance is a marker of liver tumors such as hepatoblastoma. Increasing levels of AFP may indicate the development of this tumor. Abdominal ultrasound can detect abnormal growths and masses in the abdomen such as Wilms tumor, hepatoblastoma, neuroblastoma, and adrenal carcinoma. The frequency of these tests varies in different locations but are often done every few months and the frequency may decrease as the child grows older and the risk of tumor development decreases. Surveillance can be stopped in late childhood (specific age depends on geographical location). Tumor surveillance is still very important in individuals suspected to have BWS based on their symptoms and negative genetic testing. Negative genetic testing does not mean that there is no risk of tumor development.

The highest risk associated with BWS is in the early years of life. Infants with BWS are at increased risk of complications such as preterm birth or risk of injury during vaginal delivery due to their larger size. Severe, untreated low blood sugar levels may have lifelong effects on development. However, if recognized and treated early, it usually does not have any long-term adverse effects. With close monitoring, potential complications such as embryonal tumors can be identified and treated early on. The prognosis after childhood is generally good. Adults with BWS may have some health needs depending on their specific features such as any kidney or heart abnormalities. While the risk of developing embryonal tumors is much lower after childhood, it has been reported. 

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