Beckwith-Wiedemann Syndrome Clinical Presentation

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

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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.

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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.

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