Beckwith-Wiedemann syndrome (BWS) is a growth disorder characterized by macrosomia, macroglossia, visceromegaly, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly). Early death may occur from complications of prematurity, hypoglycemia, cardiomyopathy, macroglossia, or tumors. However, the previously reported mortality of 20% is likely an overestimate given better recognition of the disorder along with enhanced treatment options. Macroglossia and macrosomia are generally present at birth but may have postnatal onset. Growth rate slows around age seven to eight years. Hemihyperplasia may affect segmental regions of the body or selected organs and tissues.
A provisional diagnosis of BWS based on clinical assessment may be confirmed by molecular/cytogenetic testing. Cytogenetically detectable abnormalities involving chromosome 11p15 are found in 1% or fewer of affected individuals. Clinically available molecular genetic testing can identify epigenetic and genomic alterations of chromosome 11p15 in individuals with BWS: (1) loss of methylation on the maternal chromosome at imprinting center 2 (IC2) in 50% of affected individuals; (2) paternal uniparental disomy for chromosome 11p15 in 20%; and (3) gain of methylation on the maternal chromosome at imprinting center 1 (IC1) in 5%. Methylation alterations that are associated with microdeletions or microduplications in this region are associated with high heritability. Sequence analysis of CDKN1C identifies mutations in approximately 40% of familial cases and 5%-10% of cases with no family history of BWS.
Beckwith-Wiedemann syndrome is associated with abnormal regulation of gene transcription in the imprinted domain on chromosome 11p15.5. Most individuals with BWS are reported to have normal chromosome studies or karyotypes. Approximately 85% of individuals with BWS have no family history of BWS while approximately 15% have a family history consistent with autosomal dominant transmission of BWS. Children of subfertile parents conceived by assisted reproductive technology (ART) may have an increased risk for imprinting disorders, including BWS. Identification of the underlying genetic mechanism causing BWS permits better estimation of recurrence risk. Prenatal screening for pregnancies not previously known to be at increased risk for BWS by ultrasound examination and maternal serum alpha-fetoprotein assay may lead to the consideration of chromosome analysis and/or molecular genetic testing. Specific prenatal testing is possible by chromosome analysis for families with an inherited chromosome abnormality or by molecular genetic testing for families in which the molecular mechanism of BWS has been defined.