The symptoms of BWS vary greatly from case to case. Some individuals may be mildly affected; others may have serious complications. The wide range of potential symptoms (clinical spectrum) can affect many different organ symptoms of the body. Affected individuals will 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.
Most infants with BWS are born prematurely, but still have an excessive birth weight (macrosomia). In fact, most infants with BWS are above the 97th percentile in weight for gestational age. Still, overgrowth may occur as late as 1 year of age. Overgrowth continues throughout childhood and slows around 7 or 8 years of age. In approximately 25 percent of cases, abnormal enlargement of one side or structure of the body (hemihyperplasia) may occur, resulting in unequal (asymmetric) growth. Hemihyperplasia refers specifically to abnormal number and accumulation of cells (proliferation) resulting in asymmetric overgrowth. A related term, hemihypertrophy, refers to overgrowth due to abnormally large cell size.
Additional common symptoms associated with BWS include an abnormally large tongue (macroglossia), advanced bone age, defects of the abdominal wall, and abnormally large internal organs (organomegaly). Macroglossia can cause difficulties in speaking, feeding and breathing.
Abdominal wall defects include a severe condition called omphalocele (sometimes called exomphalos), in which part of an infant’s intestines and abdominal organs protrude or stick out through the bellybutton. 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) resulting in a pot-bellied appearance.
The internal organs of affected individuals can become abnormally enlarged. 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) due to excessive secretion of the hormone insulin by pancreatic islets. (Insulin helps to regulate blood glucose levels by promoting the movement of glucose into bodily cells.) Most cases of neonatal hypoglycemia associated with BWS are mild and transient. However, without proper detection and appropriate treatment, neurological complications may result.
In addition to enlargement of the tongue, 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, 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, consisting of abnormal clusters of small blood vessels (capillary nevus flammeus). Such lesions typically become less apparent during the first year of life. 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), the formation of calcium deposits in the kidney (nephrocalcinosis), potentially impairing kidney function; 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.
BWS may also be characterized by genital defects, including enlargement of the clitoris (clitoromegaly) in females and undescended testes (cryptorchidism) and/or abnormal positioning of the urinary opening (hypospadias) in affected males. Other features associated with BWS may include abnormally increased numbers of circulating red blood cells within the first days of life (neonatal polycythemia) and/or various structural heart defects at birth (congenital heart defects), such as an abnormal opening in the fibrous partition (septum) between the upper or lower chambers of the heart (atrial or ventricular septal defects).
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) or the outer region of the adrenal glands (adrenal cortical carcinoma). Less commonly, other malignancies have been reported (e.g., neuroblastoma, rhabdomyosarcoma). The risk of malignancy is greatest before the age of 7 and tumor development is uncommon thereafter.
In approximately 85 percent of cases, there is no family history of BWS. In these cases, BWS is caused by genetic changes that appear to occur randomly (sporadically). More rarely, the disorder appears to be familial, suggesting autosomal dominant inheritance with variable expressivity and penetrance (see below).
Investigators have determined that BWS may result from various abnormalities affecting the proper expression of a gene or genes within a specific region of chromosome 11 (11p15.5). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p15.5” refers to band 15.5 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The changes affecting the genes associated with BWS may involve changes in the structure of a gene (genetic factors) or changes in the function or expression of a gene (epigenetics). Specific abnormalities associated with BWS include genetic imprinting errors, uniparental disomy and gene mutations. In approximately 15 percent of cases, no cause can be identified.
A specific process associated with BWS is known as genetic imprinting. Everyone has two copies of every gene, one received from the father and one received from the mother. In most cases, both genes are “turned on” or active. However, some genes are preferentially silenced or “turned off” based upon which parent that gene came from (genetic imprinting). Genetic imprinting is controlled by chemical switches through a process called methylation. Proper genetic imprinting is necessary for normal development. Defective imprinting has been associated with several disorders including BWS.
Imprinted genes tend to be found 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). Researchers have identified several specific imprinted genes regulated by these imprinting centers that play a role in the development of BWS. These genes include the KCNQ10T1 (LIT1) gene, the H19 gene, the IGF2 (insulin-like growth factor II) gene or the CDK1NC (p57[kip2]) gene. Additional genes (e.g., the KCNQ1 gene, the TSSC3 gene, the TSSC5 gene) are also located in this region. Further research is necessary to learn more about these genes and the complex genetic mechanisms responsible for BWS.
Individuals may develop genetic imprinting errors at IC1, specifically “overexpression” (disrupted imprinting) of the paternally-expressed, maternally-silenced IGF2 (insulin-like growth factor II) gene. As discussed above, in imprinted genes only one copy is “active” copy of certain genes in the 11p15 chromosomal region, including the IGF2 gene. However, in some individuals with BWS, both IGF2 gene copies are active, potentially causing or contributing to the overgrowth seen in many individuals with the disorder. Both IGF2 genes are active in approximately 20-50 percent of cases of BWS. When a gene is “expressed,” it means that the gene is active and producing different chemicals required for the body.
In some cases, individuals with two active IGF2 genes also have imprinting errors of the H19 gene. In these cases, the H19 gene, also mapped to the IC1 imprinting center, may also contribute to the development of BWS. Both copies of the H19 gene may be hypermethylated and improperly silenced or turned off. The H19 gene is believed to be a tumor suppressor gene.
Imprinting center 2 (IC2) is associated with KvDMR1, a chemical switch found on the KCN1Q gene. Loss of methylation at KvDMR1 leads to loss of imprinting and abnormal expression of the paternally-expressed KCNQ10T1 (long QT intronic transcript 1 [LIT1]) gene, which has been implicated in 50-60 percent of cases of BWS. The KCNQ10T1 gene may be involved in regulating expression of nearby genes. Errors of KvDMR1 are also associated with reduced expression of the CDK1NC gene and, in some cases, overexpression of IGF2.
Genetic imprinting errors may be caused by a specific chromosomal abnormality known as uniparental disomy. Approximately 20 percent of sporadic cases of BWS are caused by 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 (uniparental paternal disomy). 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. Specifically, the IGF2 gene is overexpressed and the CDK1NC is underexpressed. Uniparental paternal disomy occurs after fertilization (post-zygotic) so the risk of recurrence is extremely low.
Abnormal changes (mutations) of the CDK1NC gene have been detected in some individuals with BWS, 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 sporadic cases of BWS are found to have changes or disruptions (mutations) of the CDKN1C gene.
Approximately 40 percent of individuals with a positive history of BWS have mutations of the CDKN1C gene. The mutation is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
The symptoms and findings associated with BWS may not be manifested in all those who inherit a disease gene for the disorder (incomplete penetrance). According to reports in the medical literature, individuals who inherit the disease gene from the mother (maternal transmission) appear more likely to manifest symptoms than those who inherit the disease gene from the father (reduced penetrance with paternal transmission). In addition, in those individuals who do have disease symptoms, such features may vary greatly in range and severity from case to case (variable expressivity).
Research has shown that microdeletions affecting imprinting center 1 (IC1) of chromosome 11p15.5 may be the cause of some cases of autosomal dominant familial BWS. Microdeletions of the KCNQ10T1 (LIT1) gene have also been identified in some rare cases. 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 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 is more common in individuals with defects of IC2 or a mutation of the CDKN1C gene. Individuals with defects of IC1 or uniparental paternal disomy 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.
Some research suggests that children conceived with assistive reproductive technology (ARTs) may be at a greater risk of developing disorders resulting from genetic imprinting (such as BWS) than the general population. More research is necessary to determine the exact relationship, if any, 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 mild cases may go undiagnosed, it is difficult to determine the true frequency of BWS in the general population. Beckwith-Wiedemann syndrome is named for the physicians (Wiedemann HR, Beckwith JB) who first reported the disease entity in the 1960s.
BWS may be diagnosed or confirmed shortly after birth based upon a thorough clinical evaluation; detection of characteristic physical findings (e.g., increased weight and length, macroglossia, abdominal wall defects), specialized laboratory and imaging tests; and careful chromosomal (cytogenetic) analysis of the BWS region (i.e., chromosome 11p15).
In some cases, certain procedures may be performed before birth (prenatally) for families with a history of BWS. 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. During fetal ultrasonography, reflected sound waves are used to create an image of the developing fetus.
In newborns with BWS, regular monitoring of blood glucose levels should be performed to ensure prompt detection and treatment of hypoglycemia. Various specialized imaging and other tests may also be conducted to ensure early detection and appropriate management of other conditions that may be associated with the syndrome (e.g., congenital heart defects).
In addition, infants and children with BWS should undergo regular abdominal and kidney (renal) ultrasounds, chest x-rays, and laboratory studies (e.g., 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 of the fetus. AFP levels typically decline during infancy; however, AFP may be abnormally elevated in blood serum if certain malignancies are present.)
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. Pediatricians, surgeons, kidney specialists, dental specialists, speech pathologists, pediatric oncologists and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
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, somatostatin, corticosteroids), and/or other measures.
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 to prevent infection and serious damage to affected tissues.
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, usually between two and four years of age. Such surgery is performed if macroglossia causes dentoskeletal defects, psychosocial problems, upper airway obstruction, or difficulties swallowing, feeding or speaking. Occasionally, macroglossia will correct itself without medical intervention.
Surgery may be necessary if hemihyperplasia results in a significant difference (discrepancy) in the length of the legs. Craniofacial surgery may be required if hemihyperplasia affects the face.
If malignancies develop in association with BWS (e.g., Wilms tumor, hepatoblastoma), the appropriate treatment measures may 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.
The Beckwith-Wiedemann Registry was established to coordinate research efforts into Beckwith-Wiedemann syndrome. For more information on the Registry, contact:
Michael R. DeBaun, M.D., M.P.H.
Associate Professor of Pediatrics and Biostatistics
Washington University School of Medicine
4444 Forest Park Boulevard,
Campus Box 8519
St. Louis, MO 63108
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:
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FROM THE INTERNET
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