Beckwith-Wiedemann Syndrome

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Beckwith-Wiedemann syndrome

Definition

Beckwith-Wiedemann syndrome (BWS) refers to a disorder of overgrowth. This condition is usually characterized by large body size (macrosomia), large tongue (macroglossia), enlarged internal organs (visceromegaly), the presence of an abdominal wall defect (umbilical hernia or omphalocele ), and low blood sugar in the newborn period (neonatal hypoglycemia).

Description

Beckwith and Wiedemann initially described Beck-with-Wiedemann syndrome in the 1960s. It is also known as Wiedemann-Beckwith syndrome and exomphalos macroglossia gigantism syndrome (EMG syndrome).

BWS syndrome will frequently present prenatally with fetal macrosomia, enlarged placentas, and often more than usual amniotic fluid (polyhydramnios) that may lead to premature delivery (a baby being born more than three weeks before its due date). In the first half of pregnancy, the majority of amniotic fluid is made by the movement of sodium, chloride, and water crossing the amniotic membrane and fetal skin to surround the fetus. During the second half of pregnancy, the majority of amniotic fluid is fetal urine that is produced by the fetal kidneys. Another major source of amniotic fluid is secretion from the fetal respiratory tract. This sterile fluid is not stagnant. It is swallowed and urinated by the fetus constantly and is completely turned over at least once a day. If the fetus has an enlarged tongue (macroglossia), and cannot swallow as usual, this can lead to build-up of excess amniotic fluid. Aside from swallowing difficulties in the newborn, macroglossia can also lead to difficulties with feeding and breathing.

Approximately 75% of infants who have BWS will have an omphalocele. An omphalocele occurs when the absence of abdominal muscles allows the abdominal contents to protrude through the opening in the abdomen. This is covered by a membrane into which the umbilical cord inserts. Omphaloceles are thought to be caused by a disruption of the process of normal body infolding at three to four weeks of fetal development. Although 25% of infants with BWS do not have omphaloceles, they may have other abdominal wall defects such as an umbilical hernia or even a less severe separation of the abdominal muscles, called diastasis recti.

Fifty to sixty percent of newborns with BWS present have low blood sugar levels within the first few days of life. This is called neonatal hypoglycemia and is caused by having more than the usual number of islet cells in the pancreas (pancreatic islet cell hyperplasia). The islet cells of the pancreas produce insulin. This cluster of cells is called the islets of Langerhans and make up about 1% of the pancreas. These cells are the most important sugar (glucose) sensing cells in the body. When an individual eats a meal high in glucose or carbohydrates, this leads to a rise in blood sugar, which is then a signal for the increased insulin secretion by the islet cells of the pancreas. If too much insulin is produced, then the blood glucose levels drop too low. This is called hypoglycemia. Since glucose is the primary fuel for brain function, if hypoglycemia lasts too long, it can lead to brain damage. For this reason, detection and treatment of the hypoglycemia is extremely important. Any child born with features of this syndrome should be carefully monitored for hypoglycemia, especially during the first week of life. Occasionally, onset of hypoglycemia is delayed until the first month after birth. For this reason, the parents of a child with BWS should be taught to watch for the symptoms of hypoglycemia so that they can seek care as soon as possible.

Children with BWS have an increased risk of mortality associated with tumor development. These tumors begin development during fetal life (embryonal tumors). These malignant tumors develop in approximately 8% of children who have BWS. The most frequently seen tumors in individuals who have BWS include Wilms tumor (nephroblastoma) and hepatoblastomas. Wilms tumor is a tumor that arises in the kidney and consists of several embryonic tissues. Wilms tumor accounts for 80% of all kidney tumors in children. The peak incidence occurs between two and three years of age, but can be present from infancy to adulthood.

Hepatoblasomas are tumors that arise in the liver during fetal development and is the most common primary liver tumor in infancy and childhood. A wide variety of other tumors, both malignant and benign, are also seen in individuals who have BWS and include, but are not limited to, nervous system tumors (neuroblastomas), adrenal gland tumors, and tumors that commonly occur in the head and neck (rhabdomyosarcoma). The increased risk for tumors appears to be concentrated in the first eight years of life, consistent with the embryonic nature of these tumors. In patients who have BWS, tumor development is not common after age eight.

Hemihyperplasia of a lower extremity or of the whole half of the body can be present. For example, one leg may be longer than the other leg. If hemihyperplasia is present, it may be recognized at birth and may become more or less obvious as a child grows. The risk of tumor development increases significantly when hemihyperplasia is present. While only 13% of affected individuals have hemihyperplasia, 40% of those with neoplasms have hyperplasia. Most patients with BWS remain at or above the 95th percentile for length through adolescence. Advanced bone age can be identified on x-ray examination. Growth rate usually slows down at around age seven or eight. After nine years of age, the average weight remains between the 75th and 95th percentile. Although height, weight, skeletal, and dental maturity may be above average for years, growth rate gradually slows down and eventually children reach average height and normal proportions. Puberty occurs at a usual time.

Another feature includes unusual linear grooves within the ear lobes and/or a groove or pit on the top of the outer ear. Facial characteristics may include prominent eyes (exophthalmos), "stork bite" birth marks (telangiectatic nevi) of the upper half of the face, and "port wine stain" birth marks (facial nevus flammeus) on the face.

Genetic profile

The genetics of BWS is complex. Approximately 85% of individuals who have BWS have no family history of BWS and have a normal karyotype . Of these patients, approximately 20% have paternal uniparental disomy for chromosome 11p15. Uniparental disomy occurs when an individual receives two copies of a chromosome, part of a chromosome, or a gene from one parent, as opposed to receiving one copy from each parent. In this situation, the amount of gene expression can be changed and cause a disease or disorder. Approximately 5-10% of patients who have no family history and a normal karyotype have a gene change identified near 11p15, called p57(KIP2). This gene region, p57(KIP2), is a tumor suppressor region, meaning that its presence suppresses tumor development, but that the loss of a normally functioning region could lead to tumor development and potentially lead to BWS. The IGF-2 (insulin-like growth factor-2) gene is also in this region. Both uniparental disomy and a gene mutation result in dosage changes of the normal functioning genes, resulting in overexpression and subsequently increased growth and tumor risk. When a gene change in the p57(KIP2) region is found in either of the parents of the affected child, the chance for a future child to have BWS could be as high as 50% with each future pregnancy. The remaining 70% of individuals who have BWS, no family history, and a normal karyotype, have no identifiable cause for BWS. The chance for other family members to be affected in this case is expected to be low.

Approximately 10-15% of individuals who have BWS have a positive family history and a normal karyo-type. Of these families, up to 50% may have an identifiable gene change in the p57 region. If a female carries this gene change, then she has a 50% chance with each pregnancy for having a child with BWS. If a male carries the gene change, the chance for having an affected child is increased, but specific risks are not yet available. Up to 50% of individuals with a positive family history and a normal karyotype do not have an identifiable gene change in the p57 region. In this situation, the chance for the parents to have another affected child is as high as 50%.

Approximately 1-2% of patients with BWS have a detectable chromosome abnormality. In patients who have a translocation or a duplication of 11p15 detected on their karyotype, the parents' chromosome analysis should be analyzed. Depending upon the results of the parents' chromosome analysis, there could be up to a 50% chance of having an affected child with BWS.

Demographics

The reported incidence for BWS is approximately one in 14,000, although this is likely to be an underestimate because of undiagnosed cases. BWS is not found more commonly in any particular sex or geographic region and has been reported in a wide variety of ethnic backgrounds.

Signs and symptoms

Major signs or symptoms include: macrosomia, macroglossia, abdominal wall defect, visceromegaly, embryonal tumors, hemihyperplasia, ear lobe creases or ear pits, renal abnormalities, and rarely cleft palate.

Minor signs and symptoms include: polyhydramnios, prematurity, neonatal hypoglycemia, advanced bone age, heart defects, hemangioma, facial nevus flammeus, and the characteristic facial features, which include underdeveloped midface and possible soft-tissue folds under the eyes.

Diagnosis

BWS is diagnosed primarily by the identification of clinical signs and symptoms. Although there is no official diagnostic criteria for BWS, most would agree that a diagnosis requires the presence of three major findings, or at least two major findings and one minor finding. For the purposes of diagnosis, a major finding would also include a family history of BWS.

When considering the diagnosis of BWS, several other syndromes should also be considered (differential diagnosis). These include, but are not limited to, infant of a diabetic mother, Simpson-Golabi-Behmel syndrome , Perlman syndrome, Sotos syndrome , and Costello syndrome .

If a couple has had a child affected with BWS and an identifiable gene change in the p57 region has been identified, or if a chromosome abnormality is detected by chromosome analysis, then prenatal testing through chorionic villus sampling (CVS) or amniocentesis is possible. If this is not possible, then potentially, detailed ultrasound examination could help to reassure parents that the signs and symptoms of BWS are not present (such as omphalocele, macroglossia, and macrosomia). If any of these signs or symptoms are present, and the couple has had a previously affected child, then it would be very likely that the present pregnancy is affected as well.

If a couple has not had a previously affected child and has had an ultrasound examination that identifies an omphalocele, then chromosome analysis should be offered to rule out a chromosome abnormality and to look for the abnormal chromosome findings associated with BWS. If chromosome results are normal, BWS is still a possible cause for the ultrasound findings.

Treatment and management

Early treatment of hypoglycemia is important to reduce the risk of central nervous system damage. Most cases of hypoglycemia are mild and will resolve shortly with treatment, however, some cases may be more difficult. Treatment for hypoglycemia may include steroid therapy, which is usually required for only one to four months.

If an infant has an abdominal wall defect, such as an omphalocele, surgery is usually performed soon after birth to repair the defect. For very large omphaloceles, a several stage operation is performed. The treatment and management of the omphalocele depends upon the presence of other problems and is very specific to each individual.

A cardiac evaluation is recommended prior to surgery or if a heart defect is suspected by clinical evaluation. Cardiomegaly is frequently present, but usually resolves without treatment.

Non-malignant kidney abnormalities, including renal cysts and hydronephrosis, occur in approximately 25% of patients. A consult with a pediatric nephrologist would be recommended for patients who have structural renal abnormalities, including any evidence of renal calcium deposits on ultrasound examination.

To screen for tumors, a baseline MRI (magnetic resonance imaging) or CT (computed tomography) examination of the abdomen is recommended for individuals believed to have BWS. To screen for Wilms tumor and other embryonal tumors, abdominal ultrasound is recommended. Blood pressure should also be monitored, as approximately 50% of people with Wilms tumors may have associated hypertension. Because tumor development may occur at any time, though usually before eight years of age, the screening recommendations are that abdominal ultrasound be performed every three to six months until eight years of age, and then annually until growth is complete. In addition to ultrasound, screening for hepatoblastoma is accomplished by serial measurements of the serum alpha-fetoprotein (AFP) levels during these years as well. Elevated levels of serum AFP are present 80-90% of the time when a hepatoblastoma is present. Alpha-fetoprotein is a protein produced by the fetal liver. Concentrations of this protein fall rapidly during the first few weeks after birth and reach adult levels by six months of age. These adult levels are approximately 2-20 ng/ml. Thus, the presence of elevated levels in children and adults usually indicates tumor development. Abnormal AFP levels should be followed with an abdominal CT examination looking for evidence of a tumor in the liver.

Surgical removal is the primary treatment for hepatoblastoma; however, in tumors that cannot be removed, chemotherapy is performed.

Treatment for Wilms tumor is often only surgical removal of the tumor; however, in some cases chemotherapy and radiation therapies are necessary, depending upon the stage of disease and the characteristics of the tumor.

Macroglossia may need to be addressed with the possibility of surgery. The large tongue may partially block the respiratory tract and lead to problems such as difficulty breathing and feeding. In most cases, the tongue growth slows over time and eventually the tongue can be accommodated. Dental malocclusion and a prominent jaw are secondary to the macroglossia. In rare cases, surgery to reduce tongue size is needed and is usually performed between two and four years of age.

Prognosis

After dealing with initial neonatal issues such as hypoglycemia, feeding, and respiratory problems, prognosis is usually good. Infants with BWS syndrome have an approximately 20% mortality rate. This is mainly due to complications stated above, and also includes complications of prematurity and omphalocele. The prognosis with repaired omphalocele is good. The majority of deaths in cases of omphalocele are usually associated with other anomalies or respiratory insufficiency. Respiratory insufficiency can occur in patients with omphaloceles if the omphalocele is so large that prenatal lung development cannot occur as usual. Respiratory insufficiency can also occur because of prematurity.

Tumor survival rates for Wilms tumor and for hepatoblastoma are as follows. In general, the four-year survival of all patients who have Wilms tumor with favorable histology approaches 90%. For hepatoblastomas, the combination of surgery and chemotherapy has achieved disease-free survival rates of 100% for stage I, 75% for stage II, and 67% for stage III hepatoblastomas.

In children who have BWS, development is usually normal if there is no history of significant, untreated hypoglycemia. After childhood, complications for patients with BWS are uncommon and prognosis is good.