Beckwith-Wiedemann Syndrome 

Updated: Apr 03, 2018
Author: Jennifer M Kalish, MD, PhD; Chief Editor: Robert P Hoffman, MD 

Overview

Practice Essentials

Beckwith-Wiedemann Syndrome (BWS) was first characterized by Dr. J. Bruce Beckwith and Dr. Hans-Rudolf Wiedemann in the early 1960s. Patients were first noted to have abdominal wall defects, macrosomia, macroglossia, and enlarged adrenal glands. Since then, clinical presentation has expanded to recognize hemihypertrophy/lateralized overgrowth, hyperinsulinism, omphalocele, and organomegaly as classic features of BWS. Additionally, it is now recognized that there is a range of clinical features seen in patients with BWS. Presentation of BWS occurs on a spectrum ranging from isolated asymmetry to classic features of BWS.[1]

Pathophysiology

Beckwith-Wiedemann Syndrome (BWS) is a pediatric cancer predisposition disorder caused by changes in the imprinted gene loci on chromosome 11p15. Patients develop BWS as a result of the misregulation of key gene regions; the resulting misexpression of growth genes leads to the overgrowth that characterizes the condition.

While most autosomal genes are expressed biallelically, imprinted genes are expressed either from the maternal or paternal allele. These genes are regulated by specific regions near the genes called imprinting control regions (ICRs), which contain epigenetic marks (methylation) that coordinate gene expression. BWS is caused by genetic or epigenetic changes that disrupt the parent-of-origin specific expression of these genes.[2, 3] Most commonly, BWS is caused by epigenetic modifications to methylation at ICRs. BWS can also be caused by mutations in the genetic sequence, deletions, duplications in the region or chromosomal rearrangements.

The imprinted gene regions involved in BWS are H19/IGF2 and CDKN1C/KCNQ1OT1, all genes implicated in growth during early development. H19 encodes a long noncoding RNA that is maternally expressed; it is believed to act as a tumor suppressor. IGF2, or insulin-like growth factor 2, is a paternally expressed protein-coding gene. IGF2 is highly active during fetal development and acts as a growth promoter. CDKN1C, or cyclin-dependent kinase inhibitor 1C, is a gene that encodes a protein implicated in cell cycle regulation. KCNQ1OT1, or potassium voltage-gated channel subfamily Q member 1 opposite transcript 1 is the antisense transcript of the protein-coding gene KCNQ1. KCNQ1OT1 is implicated in regulating other growth genes.[4]

BWS can be caused by several different epigenetic or genetic changes at these loci. Causes can include changes to levels of methylation at the ICRs, paternal uniparental disomy (pUPD) of chromosome 11p15, chromosomal rearrangements involving the 11p15.5 region, point mutations in CDKN1C, or microdeletions in ICRs.[5] In cases where BWS is caused by epigenetic modifications to the genome, occurrence is sporadic and is generally not inherited. Risk of recurrence is the same as in the general population. Cases of BWS with a genetic cause may be inherited, though presentation depends on the parent of transmission.

Epidemiology

Frequency

Incidence is estimated to occur in 1 in 10,500 live births in the general population.[6] As individuals with milder phenotypes often go undiagnosed, the incidence may be higher.

The incidence of BWS in children conceived through assistive reproductive technology is about 1:1200.[6]

Mortality/Morbidity

Based on current data, patients with BWS have an increased tumor risk during childhood, periodic screening allows early detection and intervention. Complications related to BWS features such as omphalocele, hyperinsulinism, macroglossia may arise and require additional medical attention. Lifespan is anticipated to be normal. There is currently limited data in adults.

Race

No race predilection is observed.

Sex

No sex predilection is noted.

Age

BWS is a congenital disorder that is commonly diagnosed in early childhood. Patients with BWS have an increased risk of developing embryonal tumors in childhood. Particularly, patients with BWS have an increased risk of developing hepatoblastoma before 4 years of age and Wilms tumor before 7 years of age.[7] Clinical features of BWS typically decrease with age.

 

Prognosis

Most patients with BWS have a normal life expectancy and generally do not develop serious medical problems in adulthood as a result of the condition.

About half of patients with BWS are large in height and weight for their age in early childhood, though adults with BWS may not be unusually tall.[1] Patients with BWS have increased risk of embryonal tumors, notably hepatoblastoma and Wilms tumor in childhood. Omphalocele and abdominal wall defects often either resolve or are repaired through surgery. Macroglossia may also be addressed with tongue-reduction surgery to remedy feeding, speaking, or breathing concerns, although many cases of macroglossia resolve without surgery.

Patient Education

Patients should be directed to either the NORD or NIH entries on Beckwith-Wiedemann syndrome.[8, 9]

 

Presentation

History

Clinicians taking the history of a patient with Beckwith-Wiedemann syndrome should note any family history of childhood cancer, hemihypertrophy, macroglossia, or other clinical features of BWS. Clinicians should refer patients to specialists for features that pose additional health concerns, such as hyperinsulinism or macroglossia.

Physical

Patients with Beckwith-Wiedemann syndrome often have some or many of the following characteristics. Based on the new BWS consensus scoring system, cardinal features are awarded 2 points each and suggestive features are awarded 1 point each. A total of 4 points is sufficient for a clinical diagnosis. Greater than 2 points suggests the need for genetic testing for BWS. Note that macrosomia is no longer a cardinal feature of BWS because half of patients with molecularly confirmed BWS are not larger in size.[1, 10] Diagnosis and testing for cases of isolated omphalocele are left at the discretion of the physician as omphaloceles can be seen independent of BWS.

Cardinal features of BWS include[11, 12, 13] :

  • Macroglossia
  • Hyperinsulinism
  • Omphalocele
  • Lateralized overgrowth/hemihypertrophy – typically presented as asymmetric muscle bulk, rather than length
  • Multifocal Wilms tumor/nephroblastomatosis
  • Pathology findings including adrenal cortical cytomegaly, placental mesenchymal dysplasia, or pancreatic adenomatosis

Suggestive features of BWS include:

  • Birth weight > 2 SDS above mean
  • Facial nevus simplex
  • Polyhydramnios and/or placentomegaly
  • Ear creases and/or pits
  • Transient hypoglycemia
  • Embryonal tumors (hepatoblastoma, isolated Wilms tumor, neuroblastoma, pheochromocytoma, rhabdomyosarcoma, adrenocortical carcinoma)
  • Nephromegaly and or hepatomegaly
  • Umbilical hernia/diastasis recti

Common Complications

Tumor growth

Patients with BWS have an increased risk of tumor development. Wilms tumor and hepatoblastoma are the most common tumor types. Patients’ tumor risk is dependent upon molecular diagnosis. Other tumors such as adrenal cortical carcinoma, neuroblastoma, rhabdomyosarcoma, pheochromocytoma and pancreatoblastoma are rare, but can occur.

Hypoglycemia and Hyperinsulinism

About 50% of children with BWS have hypoglycemia and therefore patients with diagnosed BWS should be evaluated for hypoglycemia. Hypoglycemia in most BWS newborns generally resolves within the first few days of life. However, in about 5% of patients that have hyperinsulinism, the severe prolonged hypoglycemia requires escalated therapy ranging for medication (diazoxide) to partial pancreatectomy.[7] Fasting studies should be performed if hyperinsulinism is considered. Hyperinsulinism is more common in patients with paternal uniparental isodisomy (pUPD) and in patients with IC2 loss of methylation. Management should be monitored in conjunction with a center with experience with hyperinsulinism.

Causes

Beckwith-Wiedemann syndrome is caused by genetic or epigenetic mutations at imprinting loci in chromosome 11p15.5. Imprinted genes are expressed in a parent-of-origin specific fashion. Specifically, while most genes are biallelically expressed, imprinted genes are expressed monoallelically, from either the maternal or paternal chromosome. Expression in these loci is controlled by biochemical changes (methylation) on regions within the loci known as imprinting control regions (ICRs). ICRs are differentially methylated between maternal and paternal alleles; this differential methylation directs parent-of-origin specific gene expression.

Common causes of Beckwith-Wiedemann syndrome include genetic or epigenetic changes to these control regions that result in the disruption of the normal expression of growth genes at these loci. The imprinted regions involved in Beckwith-Wiedemann syndrome are the KvDMR/CDKN1C (also known as Lit1) and H19/IGF2 regions. CDKN1C encodes a cell cycle regulator and tumor suppressor while IGF2 encodes a growth promoting factor. H19 is a non-coding RNA believed to play a part in inhibiting growth. CDKN1C and H19 are normally expressed solely from the maternal allele, while IGF2 is expressed paternally.[4, 8]

Imprinting center 2 (IC2) controls expression of the KvDMR/CDKN1C region while imprinting center 1 (IC1) controls expression of the H19/IGF2 region. In the KvDMR /CDKN1C region, IC2 on the maternal allele is methylated while paternal IC2 is unmethylated. For the H19/IGF2, methylation occurs on paternal IC1 while maternal IC1 is unmethylated. Maternal loss of methylation on IC2 causes BWS, likely through downregulation of CDKN1C. Maternal gain of methylation on IC1 also results in BWS, as this change upregulates expression of the growth promoting IGF2.[4]

Epigenetic causes of BWS include gain or loss of methylation on the ICRs. Loss of methylation on the maternal allele of IC2 is the most prevalent cause of BWS, accounting for 50-60% of cases.[1] Gain of methylation on the maternal allele of IC1 can also cause BWS, accounting for 5-10% of cases.

About 20% of cases of BWS are caused by paternal uniparental disomy (pUPD) of 11p15. Patients with pUPD have two paternal copies of 11p15; this results in both loss of methylation on IC2 as well as gain of methylation on IC1. This change is typically present in some cells and not others in different regions of the body leading to a more variable phenotype.

Other possible genetic causes include maternally inherited point mutations in CDKN1C, paternal duplications in 11p15.5, microdeletions in either ICR1 or ICR2, or chromosomal rearrangements involving the 11p15.5 region. Changes involving gene mutations, deletions or duplications are rarer than the diagnoses listed above. Genetic and epigenetic changes all result in the BWS overgrowth phenotype through the overexpression of growth promotion factors such as IGF2, or the under-expression of growth restriction factors such as CDKN1C or H19.

For most cases where BWS is caused by spontaneous epigenetic alterations such as methylation changes, risk of inheritance or recurrence of the disease is no higher than that of the risk for the general population. Cases with a genetic basis may be heritable if germline cells are affected. Manifestation of BWS in the next generation depends upon the parent of transmission. To date pUPD has not been reported as heritable.

Patients with BWS have higher risk of developing embryonal tumors such as hepatoblastoma or Wilms tumor. Overall the risk is between 5-10% but this risk is stratified based on molecular diagnosis. The tumor risks by molecular diagnosis are as follows[14] :

IC2 loss of methylation (LOM): 2.5-3.1%

IC1 gain of methylation (GOM): 22.8-28.6%

pUPD: 13.8-17.3%

CDKN1C: 6.9-8.8%

Negative genetic testing: 6.7%

Patients with CDKN1C mutations also have 2.8% risk of developing neuroblastoma.

 

DDx

Diagnostic Considerations

The different molecular causes of BWS have varying tumor and health risks. Due to the stratification of risk, it is important for patients with Beckwith-Wiedemann syndrome to be tested for genetic and epigenetic alterations on chromosome 11 to appropriately assess health concerns. BWS is a mosaic disorder; as such not every cell in every tissue type may be affected. Affected patients may receive negative genetic testing results if samples tested include only unaffected cells. As a result of this mosaicism, genetic or epigenetic changes are measureable in approximately 80% of affected individuals.

Diagnosis of Beckwith-Wiedemann syndrome can be challenging due to both the variable clinical presentation and the often mosaic nature of the molecular changes. Clinical features, genetic testing results, and family history should all be considered during assessment. In the absence of positive genetic testing results, a diagnosis may be reached by considering the presentation of clinical features. Listed in the Physical section are the cardinal and suggestive features, as well as the scoring system for determining a clinical diagnosis. If a patient displays enough physical characteristics to result in a clinical diagnosis of BWS, tumor screening is recommended, regardless of testing results.

Differential Diagnoses

  • Perlman syndrome

  • Simpson-Golabi-Behmel

  • Sotos syndrome

  • Weaver syndrome (Weaver-Smith)

 

Workup

Approach Considerations

Children with suspected BWS should be evaluated by a geneticist familiar with BWS. The range of clinical presentations of BWS should be considered and referral is recommended if any of the cardinal features are observed. If BWS is suspected, genetic testing should be done to appropriately ascertain health risks. BWS can also be diagnosed clinically, so patients with enough cardinal or suggestive features may still be diagnosed positively given significant presentation of features despite normal molecular testing. A clinical diagnosis also suffices if testing is not possible.

Laboratory Studies

Genetic testing is recommended for patients with suspected Beckwith-Wiedemann syndrome:

  • Methylation analysis for chromosome 11p15: These tests evaluate levels of methylation at imprinting centers 1 and 2.
  • SNP array (microarray): These tests survey whether large deletions or duplications exist at the 11p15 region. They can also detect paternal uniparental disomy.
  • CDKN1C gene sequencing: Gene sequencing can identify mutations in CDKN1C. Patients with mutations in CDKN1C also have a 2.8% risk of developing neuroblastoma.

Tumor screening

Tumor screening is recommended starting at the time of diagnosis. In the United States, in accordance with the American Association of Cancer Research (AACR) guidelines, all children with greater than a 1% risk of developing a tumor should be screened. As such, all patients with molecularly or clinically diagnosed BWS as well as patients with hemihypertrophy should be routinely screened.[15]

Tumors most frequently seen in BWS patients are Wilms tumor and hepatoblastoma. Wilms tumor is most easily detectable by ultrasound. Patients have increased risk of Wilms tumor until age 7, when the risk decreases to that of the general pediatric population. Hepatoblastoma are detectable by measuring alpha-fetoprotein (AFP) levels in blood, as well as by abdominal ultrasound. Risk of hepatoblastoma is highest in the first year of life and decreases with age until age 4, when the risk is the same as the general population.

Tumor screening guidelines are as follows[15]

Ultrasound Screening

  • Full abdominal ultrasound every three months until age 4 years

  • Renal ultrasound every three months from age 4-7 years

Alpha-fetoprotein (AFP) screening

  • AFP measurements every three months until age 4 years.

    In patients with BWS, AFP levels may be high after birth and decrease with age. AFPs should be followed over time as the overall trend of decreasing AFP values is more important than the value of any one measurement. If values increase drastically, further testing should be done to rule out the possibility of hepatoblastoma.

    Children with a prenatal or perinatal diagnosis of BWS should have their blood sugar evaluated at birth to ensure proper detection and treatment of hypoglycemia.

Imaging Studies

To screen for tumor development, regular ultrasound screenings are recommended[15] :

Ultrasound Screening

  • Full abdominal ultrasound every three months until age 4 years

  • Renal ultrasound every three months from age 4-7 years

Procedures

If problems in speaking, feeding, or breathing arise due to macroglossia, a glossectomy or partial glossectomy may be required. A plastic surgeon familiar with Beckwith-Wiedemann syndrome should be consulted. Tumor development may also require surgical intervention. Leg length difference may require consultation with an orthopedic surgeon. In cases of severe hyperinsulinism, medical management or in some cases a partial pancreatectomy may be necessary. Consultation with an endocrinologist familiar with BWS is advisable and an inpatient fasting study at a center specializing in BWS may be necessary.

 

Treatment

Medical Care

Medical care is determined by the type and severity of BWS features. Consultation with specialists may be necessary depending on the nature and severity of the patient’s characteristics.

Regardless of specific presentation, all diagnosed children should be screened for tumor growth. Current screening recommendations are as follows[15] :

Ultrasound Screening

  • Full abdominal ultrasound every three months until age 4 years

  • Renal ultrasound every three months from age 4-7 years

Alpha-fetoprotein (AFP) screening

AFP measurements every three months until age 4 years.

Patients with Beckwith-Wiedemann syndrome (BWS) may require escalated care to manage persistent hypoglycemia. This may include treatment with diazoxide, octreotide, continuous feeds or in some cases partial pancreatectomy.[7] Consultation with experts in managing hyperinsulinism is recommended.

Surgical Care

Embryonal tumors require appropriate oncologic treatment modalities, which often include nephrectomy.

Nephron-sparing partial nephrectomy is feasible if embryonal renal tumors are detected early, highlighting the need for frequent ultrasonographic screening.

Depending on the severity of macroglossia, surgical intervention may be required.

Pancreatectomy may be required for patients with persistent and severe hyperinsulinism.

Consultations

Patients with Beckwith Wiedemann syndrome present with a variety of clinical features and may require consultation with a variety of healthcare providers. Some may include:

  • Pediatrician: management of general pediatric concerns

  • Geneticist: diagnosis and care coordination for BWS features

  • Endocrinologist: management of hypoglycemia/hyperinsulinism

  • Feeding specialist: feeding evaluation and optimization with macroglossia

  • Oncologist: management of tumor screening

  • Orthodontist: evaluation of tooth and jaw development with macroglossia

  • Orthopedic surgeon: evaluation and management of hemihypertrophy/lateralized overgrowth

  • Otolaryngologist: evaluation of the airway, tonsils, and adenoids with macroglossia

  • Plastic surgeon: evaluation for and management of macroglossia

  • Pulmonologist: evaluation for obstructive sleep apnea with macroglossia

  • Speech therapist: speech therapy with macroglossia

Diet

Children with feeding issues may require evaluation for hemiglossectomy; other dietary modifications are determined by the child’s individual health concerns

Activity

Patients with Beckwith-Wiedemann syndrome do not require activity restrictions.

Further Outpatient Care

Further care should include routine visits with a pediatrician or primary care specialist to monitor clinical features and child development.

Patient-specific features may necessitate consultation with specialists.

Patients with Beckwith Wiedemann syndrome should be routinely screened for tumor development. Screening should be monitored by a physician familiar with BWS tumor screening and should include a geneticist, oncologist, or pediatrician. For patients without major complications associated with BWS, yearly checkups with a geneticist are typically recommended.

Transfer

Maintain airway and euglycemia (with intravenous dextrose) en route to a tertiary care center.

Deterrence/Prevention

Cancer develops in approximately 5-10% of children with Beckwith-Wiedemann syndrome; as such, guidelines are to screen all children diagnosed with BWS either molecularly or clinically. The risk of cancer is age-dependent: the risk of hepatoblastoma is higher in patients younger than 4 years, while the risk of Wilms tumor is elevated until age 7 years. After, the risk becomes that of the general population.[16] The recommended tumor screening is as follows:

Ultrasound Screening

  • Full abdominal ultrasound every three months until age 4 years

  • Renal ultrasound every three months from age 4-7 years

Alpha-fetoprotein (AFP) screening

  • AFP measurements every three months until age 4 years.

    Ultrasound screening can detect both hepatoblastoma and Wilms tumor, the most common cancers in patients with BWS. Alpha-fetoprotein is a marker of liver growth. AFP levels are much higher than normal after birth and decrease with age. The overall trend of decreasing AFP values is more important than the value of any one measurement. If values increase drastically, further testing should be done to rule out the possibility of hepatoblastoma.

    Prenatal ultrasonography permits early detection of severely affected patients with Beckwith-Wiedemann syndrome. More critically, prenatal diagnosis allows physicians to anticipate the most serious health consequences associated with Beckwith-Wiedemann syndrome, namely, hypoglycemia and abdominal tumors. Features such as omphalocele, enlarged kidneys, large for gestational age and less commonly, macroglossia can be detected on prenatal sonograms. If any of these features are suspected, genetic testing on amniocytes is recommended. Pregnancy can be complicated by polyhydramnios (increased fluid) and placental mesenchymal dysplasia (enlarged placenta with distinct histological features).

Complications

Medical and surgical complications are possible with treatment of abdominal tumors.

Prognosis

Prognosis is good and depends primarily on the status of the airway, on early management of hypoglycemia if present, and on tumor screening.

 

Guidelines

Guidelines Summary

Patients with suspected BWS should be evaluated based on published guidelines for clinical diagnosis. Based on the new BWS consensus scoring system, cardinal features are awarded 2 points each and suggestive features are awarded 1 point each. A total of 4 points is sufficient for a clinical diagnosis. Greater than 2 points suggests the need for genetic testing for BWS. A list of cardinal and suggestive features can be found in the Physical section.[1]

Molecular testing is essential to plan and guide patient care, as tumor risk is stratified among the molecular subtypes of BWS. However, an important consideration of genetic testing is that BWS is a mosaic disorder. As such, some cell types may carry epigenetic changes while others may be normal. Thus, negative test results do not necessarily indicate that a patient does not have BWS, but rather that the cell type tested is unaffected. In lieu of a positive diagnosis, a clinical diagnosis of BWS or hemihypertrophy is sufficient to warrant tumor screening.

Tumor screening includes a full abdominal ultrasound every three months until age 4 years, and renal ultrasound from age 4-7. Additionally, alpha-fetoprotein screening is recommended every 3 months until age 4 years to screen for development of hepatoblastoma. Importantly, AFP levels may be higher at birth. AFP levels should be monitored over time and should decrease with age. Significant increases in AFP levels relative to the patient’s trend over time warrant further testing for tumor development.[15, 17]

Patients with BWS may experience other health complications including hyperinsulinism/hypoglycemia, macroglossia, hemihypertrophy, or tumor development. Further information on consultations can be found in the Consultations section.

 

Medication

Medication Summary

No medication is uniformly taken by patients with Beckwith-Wiedemann syndrome. Medications are advised based on the particular clinical presentation of the patient and depend on what traits and symptoms arise.