About Beckwith Wiedemann Syndrome

Beckwith Wiedemann Syndrome is an overgrowth disorder characterized bymacrosomia, macroglossia, organomegaly and developmental abnormalities (in particular Abdominal Wall Defects with exomphalos). Its incidence is estimated to be 1 per 13,700 live births.

BWS patients are prone to the development of embryonal tumors (most commonly Wilms’ tumor or nephroblastoma). BWS is a multigenetic disorder caused by dysregulation of Gene expression in the imprinted 11p15 chromosomal region.

Various 11p15 defects have been implicated and epigenetic defects account for about two thirds of cases. The management of patients with BWS involves the surgical cure of exomphalos and monitoring of hypoglycemia in the neonatal period. It also involves the treatment of macroglossia and the screening for embryonal tumor that can be facilitated by genotyping.

A recent series of reports suggested that assisted reproductive technology (ART) may increase the risk of imprinting disorders, and BWS in particular.

Beckwith-Wiedemann syndrome is a condition that affects many parts of the body. It is classified as an overgrowth syndrome, which means that affected infants are considerably larger than normal (macrosomia) and tend to be taller than their peers during childhood. Growth begins to slow by about age 8, and adults with this condition are not unusually tall.

In some Children with Beckwith-Wiedemann syndrome, specific parts of the body on one side or the other may grow abnormally large, leading to an asymmetric or uneven appearance. This unusual growth pattern, which is known as hemihyperplasia, usually becomes less apparent over time.

The signs and symptoms of Beckwith-Wiedemann syndrome vary among affected individuals. Some children with this condition are born with an opening in the wall of the abdomen (an omphalocele) that allows the abdominal organs to protrude through the belly-button.

Other abdominal wall defects, such as a soft out-pouching around the belly-button (an umbilical hernia), are also common. Some infants with Beckwith-Wiedemann syndrome have an abnormally large tongue (macroglossia), which may interfere with breathing, swallowing, and speaking.

Other major features of this condition include abnormally large abdominal organs (visceromegaly), creases or pits in the skin near the ears, low blood sugar (hypoglycemia) in infancy, and kidney abnormalities.

Children with Beckwith-Wiedemann syndrome are at an increased risk of developing several types of cancerous and noncancerous tumors, particularly a form of kidney cancer called Wilms tumor and a form of liver cancer called hepatoblastoma. Tumors develop in about 10 percent of people with this condition and almost always appear in childhood.

Most children and adults with Beckwith-Wiedemann syndrome do not have serious medical problems associated with the condition. Their life expectancy is usually normal.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder. It is characterized by a wide spectrum of symptoms and physical findings that vary in range and severity from person to person.

However, in many individuals, associated features include above-average birth weight and increased growth after birth (macrosomia), an unusually large tongue (macroglossia), enlargement of certain internal organs (organomegaly), and abdominal wall defects (omphalocele or umbilical hernia).

BWS may also be associated with low blood sugar levels within the first few days (neonatal hypoglycemia), or beyond (hyperinsulinism), distinctive grooves in the ear lobes and other facial abnormalities, abnormal enlargement of one side or structure of the body (hemihyperplasia/hemihypertrophy) resulting in unequal (asymmetric) growth, and an increased risk of developing certain childhood cancers, most commonly Wilms tumor and hepatoblastoma.

Approximately 85 percent of people with BWS have genetic changes that appear to occur randomly (sporadically). Familial transmission occurs in approximately 10-15 percent of people with this syndrome.

Researchers have determined that BWS results from various abnormalities affecting the proper expression of certain genes that control growth within a specific region of chromosome 11.

Beckwith-Wiedemann syndrome (BWS) is a growth regulation disorder. The most common features of BWS include macrosomia (large body size), macroglossia (large tongue), abdominal wall defects, an increased risk for childhood tumors, kidney abnormalities, hypoglycemia (low blood sugar) in the newborn period, and unusual ear creases or pits. Children with BWS may also have hemihyperplasia, in which some parts of the body are larger on one side than on the other.

The major features of BWS, macrosomia and macroglossia, are often present at birth. Abdominal wall defects such as omphalocele, which causes the inside of the abdomen to protrude through the navel, are also present at birth and may require surgery before an infant leaves the hospital.

Mothers of children with BWS may have pregnancy complications, including premature delivery and polyhydramnios, meaning excess amniotic fluid. An unusually large placenta and long umbilical cord may also be present.

The increased growth rate generally slows during childhood. Intellectual development is usually normal, and adults with BWS typically do not experience any medical problems related to their condition.

Symptoms

The symptoms of BWS vary greatly from person to person. Diagnosis of BWS can be challenging because the patients are often mosaic (with the genetic changes occurring in some cells or parts of the body but not others), however external appearance is not necessarily predictive of internal effects.

This results in some individuals appearing mildly affected, while others appear more significantly affected. The wide range of potential symptoms (clinical spectrum) can affect many different organs of the body. Affected individuals may not have all of the symptoms listed below.

Many clinical features of BWS become less evident with increasing age and many adults experience normal growth and appearance. Intelligence is usually unaffected in BWS, unless associated with prolonged, untreated neonatal hypoglycemia or a chromosomal duplication.

Some infants with BWS are born prematurely, but still have an excessive birth weight (large for gestational age). Many infants with BWS are above the 97th percentile in weight for gestational age. Overgrowth continues throughout childhood (macrosomia) and slows around 7 or 8 years of age. Abnormal enlargement of one side or structure of the body

(hemihyperplasia/hemihypertrophy) may occur, resulting in unequal (asymmetric) growth. Hemihyperplasia refers specifically to an increase in number of cells (proliferation) resulting in asymmetric overgrowth. A related term, hemihypertrophy, refers to overgrowth due to abnormally large cell size.

Abdominal wall defects include an omphalocele (also known as exomphalos), in which part of an infant’s intestines and abdominal organs protrude or stick out through the belly button.

The intestines and other organs are covered by a thin membrane. Less severe defects can include protrusion of part of the intestines through an abnormal opening in the muscular wall of the abdomen near the umbilical cord (umbilical hernia), or weakness and separation of the left and right muscles (rectus muscles) of the abdominal wall (diastasis recti).

The internal organs of affected individuals can become abnormally enlarged (organomegaly). Any or all of the following organs may be affected: liver, spleen, pancreas, kidneys, or adrenal glands.

Some newborns with BWS may have low blood sugar (neonatal hypoglycemia or hyperinsulinism) due to overgrowth and excessive secretion of the hormone insulin by pancreatic islets. Insulin functions to help regulate blood glucose levels by promoting the movement of glucose into cells.

Most infants with neonatal hypoglycemia associated with BWS have mild and transient symptoms. However, without proper detection and appropriate treatment, neurological complications may result.

Children with BWS may have an enlarged tongue (macroglossia), which can cause difficulties in speaking, feeding, and breathing. In addition to an enlargement of the tongue (macroglossia), BWS may be characterized by other abnormalities of the skull and facial (craniofacial) region.

Such features may include distinctive slit-like linear grooves or creases in the ear lobes and indentations on the back rims of the ears (pits), prominent eyes with relative underdevelopment of the bony cavity of the eyes (intraorbital hypoplasia), and/or a prominent back region of the skull (occiput).

Some infants may have flat, pale red or reddish purple facial lesions at birth, most commonly on the eyelids and forehead, which consist of abnormal clusters of small blood vessels (capillary nevus flammeus).

Such lesions typically become less apparent during the first year of life. In children with hemihyperplasia/hemihypertrophy, one side of the face may appear larger than the other. Due to the mosaic nature of BWS, some children have eyes with multiple colors.

In addition, in some affected children, there may be improper contact of the teeth of the upper and lower jaws (malocclusion) and abnormal protrusion of the lower jaw (mandibular prognathism), features that may occur secondary to abnormal largeness of the tongue.

A variety of kidney (renal) abnormalities have occurred in individuals with BWS, including abnormally large kidneys (nephromegaly), improper development of the innermost tissues of the kidney (renal medullary dysplasia), and the formation of calcium deposits in the kidney (nephrocalcinosis), which could potentially impair kidney function.

Additional abnormalities include duplication of the series of tubes and ducts through which the kidneys reabsorb water and sodium (duplicated collecting system), widening of some of the small tubes and collecting ducts (medullary sponge kidney), and the presence of small pouches (diverticula) on the kidneys.

Children with BWS may have an increased risk of developing certain childhood cancers, particularly Wilms tumor (nephroblastoma), which is a malignancy of the kidney, and tumors involving the liver (hepatoblastoma). Less commonly, other malignancies have been reported (e.g., neuroblastoma, rhabdomyosarcoma). The risk of malignancy is greatest before the age of 8.

Causes

Approximately 85 percent of people with BWS have no family history of this syndrome. For these people, BWS is caused by genetic or epigenetic changes that appear to occur randomly (sporadically). More rarely, the disorder appears to be inherited.

BWS results from various abnormalities affecting the proper expression of genes that control growth within a specific region of chromosome 11.This region is referred to as the BWS critical region.

Everyone has two copies of every gene, one received from the father and one received from the mother. In most people, both genes are “turned on” or active. However, some genes are preferentially silenced or “turned off” based upon which parent that gene came from (a process known as genomic imprinting).

Genomic imprinting is controlled by marks on the DNA called methylation. Proper genomic imprinting is necessary for normal development and defective imprinting on chromosome 11 can lead to BWS. Several genes that control growth on chromosome 11 are imprinted which means that the gene is only active from the mother’s chromosome or the father’s chromosome but not both.

Imprinted genes tend to be clustered or grouped together. Several imprinted genes are found in a cluster on chromosome 11p15.5. The cluster is divided into two functional regions known as imprinting centers (IC1 and IC2).

Several specific imprinted genes regulated by these imprinting centers that play a role in the development of BWS. These genes include the H19 gene (a gene that signals not to grow), the IGF2 (insulin-like growth factor II) gene, the KCNQ10T1 (LIT1) gene, and the CDKN1C (p57[KIP2]) gene (a signal not to grow).

Increased methylation at imprinting center 1 (IC1) occurs in 2-7% of people with BWS and leads to loss of H19 expression and increased IGF2 expression. Imprinting center 2 (IC2) is associated with KvDMR, a chemical switch found on the KCNQ1 gene.

Loss of methylation at KvDMR1 occurs in about 50% of people with BWS and leads to loss of imprinting and increased expression of the paternally-expressed KCNQ10T1 (long QT intronic transcript 1 [LIT1]) gene, and loss of expression of CDKN1C.

H19 is a long noncoding RNA thought to play a role in inhibiting growth. IGF2 is a growth factor. KCNQ10T1 is a noncoding RNA and CDKN1C is a cell cycle regulator and tumor suppressor.

Genetic imprinting errors may be caused by a specific chromosomal abnormality known as uniparental disomy (UPD). Approximately 20 percent of people with sporadic BWS have uniparental disomy, an abnormality in which a person receives both copies of a chromosome (or part of a chromosome) from one parent instead of receiving one from each parent.

In BWS, both copies of chromosome 11 are received from the father (paternal uniparental disomy (pUPD)). As a result, there are too many active paternally-expressed genes in this region and not enough maternally-expressed genes.

Researchers believe that the paternally-expressed genes promote growth and that maternally-expressed genes act as tumor suppressor genes or inhibit growth. Specifically, the IGF2 gene is overexpressed and the CDKN1C is underexpressed. Uniparental paternal disomy occurs after fertilization (post-zygotic) so the risk of recurrence is extremely low.

Abnormal changes (mutations) of the CDKN1C gene have been detected in some individuals with BWS. The loss of proper expression or “underexpression” of the gene is thought to play an important role in causing the disorder. Approximately 5-10 percent of people with BWS are found to have changes or disruptions (mutations) of the CDKN1C gene.

Approximately 40 percent of individuals with a family history of BWS have mutations of the CDKN1C gene. The mutation is inherited as an autosomal dominant trait, which means that the risk of passing the abnormal gene from the parent to offspring is 50 percent for each pregnancy regardless of the gender of the child. However, CDKN1C is only made from the mother’s chromosome, so the offspring will only be affected (ie have BWS) if the mutation is passed from mother to offspring.

Research has shown that microdeletions affecting imprinting center 1 (IC1) of chromosome 11p15.5 may be the cause of familial BWS in some people. Microdeletions of the KCNQ10T1 (LIT1) gene have also been identified in some people with BWS. The exact frequency and risk of recurrence of these microdeletions is not yet known. However, these microdeletions appear to cause

BWS when inherited maternally; when inherited paternally the disorder does not develop.

In addition, in approximately 1-2 percent cases of BWS, various chromosomal abnormalities have been reported involving the 11p15.5 chromosomal region. These have included chromosomal inversions or rearrangements (translocations) or the presence of extra (duplicated) chromosomal material.

Researchers are investigating if specific causes of BWS are associated with specific symptoms (genotype-phenotype correlation). Research indicates that omphalocele and macroglossia are more common in individuals with defects of IC2 or a mutation of the CDKN1C gene. Individuals with defects of IC1 or uniparental paternal disomy (UPD) appear to be at a greater risk of developing an associated cancer such as Wilms tumor.

Children with uniparental paternal disomy are also at a greater risk of developing hemihypertrophy. More research is necessary to determine how the specific causes of BWS correlate with the various symptoms of the disorder.

Research also suggests that children conceived with assistive reproductive technology (ART), such as in vitro fertilization (IVF) may be at a greater risk of developing disorders resulting from genomic imprinting (such as BWS) than the general population. More research is necessary to determine the exact relationship between such technologies and the development of BWS.

The genetic mechanisms that cause gene mutations (alterations) resulting in BWS are complex. BWS is classified as an imprinting disorder. To understand imprinting, it is important to note that everyone inherits 2 copies of each gene, 1 from each parent. Usually, this results in both copies of the genes being expressed. However, imprinting refers to the process of deactivating 1 copy of a gene so that only a single copy is expressed normally.

Imprinting disorders are caused by inappropriate functioning of the gene expression at imprinted sites. There can be differences in this expression as well from person to person, including both copies being expressed or neither copy is expressed. Depending on the genes affected, tumor risk can range from approximately 3% to 43%.

The most common cause of BWS is a change in DNA methylation. In about 20% of BWS, a person has inherited both copies of a specific gene from his or her father, leading to some genes having increased expression and others having decreased expression. Other causes include genetic mutations (10%) and unknown reasons for about 13% to 15% of cases.

It is important for doctors to find out the specific genetic mutation involved, since that affects the specific increase of the type of tumor and the appropriate monitoring schedule.

BWS is a genetic condition related to changes in the genes of chromosome 11 (11p15.5), in an area called the short arm. This is the area of the chromosome where 2 genes are located: insulin-like growth factor II (IGF-2) and cyclin-dependent kinase inhibitor (CDKN1C). In about 85% of cases, the genetic changes that cause BWS happen sporadically, meaning it occurs by chance, in families where there is no history of the condition. In about 10% to 15 % of cases, the genetic changes may be inherited. This means that the risk for BWS can be passed from generation to generation in a family.

Diagnosis

BWS may be diagnosed or confirmed shortly after birth based on a thorough clinical evaluation, detection of characteristic physical findings (e.g., increased weight and length, macroglossia, abdominal wall defects and careful methylation testing and chromosomal (cytogenetic) analysis of the BWS region (i.e., chromosome 11p15)).

In some cases, certain procedures may be performed before birth (prenatally). For example, ultrasound imaging may allow assessment of organ size and overall size of the developing fetus and potentially reveal other findings that may be suggestive of BWS, such as increased amniotic fluid surrounding the fetus (hydramnios), enlarged placenta, omphalocele, enlarged abdominal circumference, and/or other abnormalities. If BWS is suspected, prenatal testing is available.

The diagnosis of BWS is clinical, meaning that it is based primarily on physical signs. BWS is suspected in children who are larger than expected for their age, especially if growth is not symmetrical, meaning the same on both sides. An enlarged tongue and abdominal wall defect, primarily omphalocele, are also considered to be common features.

There are many other features that may be seen in some children with BWS. However, not every child with BWS will have every feature. Features are listed as major (common) or minor (less common). It is generally agreed that at least 1 major feature and 2 minor features are required for a diagnosis of BWS:

Major Features

• Macrosomia (large body size)
• Macroglossia (large tongue)
• Omphalocele (abdomen protrudes through navel)
• Hemihyperplasia, meaning some parts of the body are larger on 1 side
• Ear lobe creases or pits
• Visceromegaly, which is the enlargement of 1 or more abdominal organ
• Embryonal tumor (Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma)
• Adrenocortical tumor (adrenal gland tumor)
• Kidney abnormalities
• Cleft palate, which is a gap in the roof of the mouth
• Family history of BWS

Minor Features

• Polyhydramnios (excessive amniotic fluid)
• Prematurity (low birth weight)
• Hypoglycemia (low blood sugar)
• Advanced bone age
• Heart problems
• Diastatsis recti, which is the separation of the right and left sides of the main abdominal muscle
• Hemangioma, a noncancerous tumor made up of blood vessels
• Facial nevus flammeus, a hemangioma of the skin, also called a “port-wine stain”
• Characteristic facial features
• Identical twins

Early diagnosis of BWS is important because children with BWS are at a higher risk for developing certain tumors, including Wilms tumor and hepatoblastoma (see below).

Genetic testing for gene mutations associated with BWS is available, but it is complex. It is recommended that all families considering genetic testing for BWS meet with a clinical geneticist, a medical doctor who has training in genetics, and a genetic counselor that can explain the tests and coordinate testing. The genetic testing methods that are currently available may be able to identify up to 80% of genetic mutations causing BWS.

Treatment

The treatment of BWS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Geneticists, pediatricians, plastic surgeons, kidney specialists, dental specialists, speech pathologists, pediatric oncologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.

In newborns with BWS, regular monitoring of blood glucose levels should be performed to ensure prompt detection and treatment of hypoglycemia. Although neonatal hypoglycemia is usually mild and temporary, its prompt detection and treatment is essential in preventing associated neurologic complications. Treatment measures may include the administration of intravenous glucose, frequent feedings, certain medications (e.g., diazoxide or octreotide), and/or surgical intervention in some cases.

In many infants with umbilical hernia, the defect may spontaneously disappear by the age of approximately one year. Surgery usually is not required unless an umbilical hernia becomes progressively larger, does not spontaneously resolve (e.g., by about three or four years of age), and/or is associated with certain complications. However, in newborns with omphalocele, surgical repair of the defect is typically required shortly after birth.

Children with macroglossia should undergo feeding evaluation and sleep studies in addition to consultations with plastic surgeons and pulmonologists if needed. Feeding difficulties caused by an abnormally large tongue (macroglossia) may be treated by the use of specialized nipples or the temporary insertion of a nasogastric tube. Some affected children may undergo tongue reduction surgery. Such surgery is performed if macroglossia causes dentoskeletal defects, psychosocial problems, upper airway obstruction, or difficulties swallowing, feeding or speaking. Macroglossia may also correct itself without medical intervention.

Orthopedic evaluation is recommended for patients with hemihyperplasia or hemihypertrophy.

In addition, infants and children with BWS should undergo regular abdominal and kidney (renal) ultrasounds, and serum alpha-fetoprotein levels as recommended to enable early detection and treatment of certain malignancies that may occur in association with BWS (e.g., Wilms tumor, hepatoblastoma). Alpha-fetoprotein (AFP) is a protein produced by the liver.

AFP levels typically decline during infancy; however, AFP may be abnormally elevated in blood serum if certain malignancies are present. The trend in AFP levels over time should be followed in children with BWS. Screening is recommended by AFPs every six weeks – three months until age 4 years and abdominal ultrasounds every 3 months until age 8 years.

If malignancies develop in association with BWS (e.g., Wilms tumor, hepatoblastoma), the appropriate treatment measures vary depending upon the specific malignancy present, grade and/or extent of disease, and/or other factors. Treatment methods may include surgery, use of certain anticancer drugs (chemotherapy), radiation therapy, and/or other measures. (For more information on Wilms tumor, choose “Wilms” as your search term in the Rare Disease Database.)

Children with cardiac, gastrointestinal, and renal abnormalities may require certain medications, surgery, or other medical interventions. These children should be referred to appropriate specialists. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.