Beckwith-Wiedemann syndrome (BWS) is a growth disorder. Clinical features commonly include: macrosomia (large body size), macroglossia (enlarged tongue), visceromegaly, omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly). Polyhydramnios may be identified during pregnancy. Infants with BWS have an approximately 20% mortality rate, mainly caused by complications of prematurely, omphalocele, and/or hypoglycemia. Macroglossia and macrosomia are generally present at birth but may have postnatal onset. The growth rate slows around seven to eight years of age. Hemihyperplasia may affect segmental regions of the body or selected organs and tissues. In addition, individuals with BWS are at an increased risk of developing embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma). Development and intelligence are typically unaffected, with the exception of mild speech delay in some individuals with severe macroglossia.
Defects in imprinted gene expression at 11p15 are associated with BWS [1,2]. Greater than 70% of cases are found to have alterations in DNA methylation at two distinct differentially methylated regions (DMRs) at 11p15. DMR1 is located within the telomeric domain (also known as ICR1) and controls the expression of two genes, IGF2 and H19. DMR2 is located within the centromeric domain (also known as ICR2) and controls the expression of the KCNQ1, CDKN1C, SLC22A1L and TSSC3 genes. Alterations in DNA methylation at either of these DMRs causes aberrant expression of these imprinted genes leading to Beckwith-Wiedemann syndrome.
BWS is typically sporadic, though inheritance has also been reported in an autosomal dominant pattern, due to other mutations. No single explanation can account for the phenotypic heterogeneity seen in patients with BWS. The recurrence risk due to methylation defects is estimated to be low.
References:1. Weksberg R, Smith AC, Squire J, Sadowski P. Hum Mol Genet. 2003; 12: R61-68.
2. Gaston V, Le Bouc Y, Soupre V, Burglen L et al. Eur J Hum Genet. 2001; 6:409-418.
3. Coffee, B, Muralidharan, K, Highsmith, WE, Lapunzina, P, and Warren, ST. Genet. Med. 2006: 8(10): 628-634.
- Individuals with a clinical diagnosis of Beckwith-Wiedemann syndrome.
- Individuals with isolated segmental hemihyperplasia.
Detection and Reference Range
Hypomethylation of DMR2 (Lit1 gene) is expected to detect up to 60-70% of individuals with BWS. Hypermethylation of DMR1 (H19 gene) is expected to detect an additional 2-13% of individuals with BWS. Therefore, the total detection rate for both DMR1 and DMR2 methylation analysis is estimated to be 62-83%.
For DMR1 (H19 gene), an increase in DNA methylation of greater than two standard deviations above the mean of normal is consistent with BWS. For DMR2 (Lit1 gene), a decrease in DNA methylation of greater than two standard deviations below the mean of normal is consistent with BWS. See Coffee et al. for explanation of reference range .
Submit only 1 of the following specimen types
Preferred specimen type: Whole Blood
Type: Whole Blood
Specimen Requirements:In EDTA (purple top) tube:
Infants (<2 years): 2-3 ml
Children (>2 years): 3-5 ml
Older Children & Adults: 5-10 ml
Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.
Specimen Requirements:OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.
Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.
- Chromosome analysis (CA, CB) and array CGH (VA) are available for children with growth disorders and congenital anomalies with or without mental retardation.
- Methylation for DMR1 (H19 gene) or DMR2 (Lit1 gene) alone is available.