NORD gratefully acknowledges Jennifer Kalish, MD PhD, Attending Physician, Division of Human Genetics, Kelly Duffy, MPH, and Carolyn Lye, The Children's Hospital of Philadelphia, for the preparation of this report.
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.
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 (11p15.5). 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.
Beckwith-Wiedemann syndrome affects males and females in equal numbers. The incidence is estimated to occur in 1 in 13,700 individuals in the general population. Because people who are mildly affected may go undiagnosed, it is difficult to determine the true frequency of BWS in the general population.
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 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.
A Beckwith-Wiedemann Registry was established to coordinate research efforts into Beckwith-Wiedemann syndrome. For more information on the Registry, contact:
Jennifer M. Kalish, MD, PhD
Division of Human Genetics
The Children’s Hospital of Philadelphia
3615 Civic Center Boulevard
Abramson Research Center, Rm 1002
Philadelphia, PA 19104
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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