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Beckwith-Wiedemann Syndrome.

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GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
2000 Mar 3 [updated 2016 Aug 11].

Author information

1
Director, Genetic Counseling, The Hospital for Sick Children, Program Director, MSc Program, Professor, Molecular Genetics, University of Toronto, Toronto, Ontario
2
Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, California
3
Geneticist, Clinical and Metabolic Genetics, Senior Associate Scientist, Research Institute, The Hospital for Sick Children, Professor, Department of Pediatrics, University of Toronto, Toronto, Ontario

Excerpt

CLINICAL CHARACTERISTICS:

Beckwith-Wiedemann syndrome (BWS) is a growth disorder variably characterized by neonatal hypoglycemia, macrosomia, macroglossia, hemihyperplasia, omphalocele, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma), visceromegaly, adrenocortical cytomegaly, renal abnormalities (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly), and ear creases/pits. BWS is considered a clinical spectrum, in which affected individuals may have many of these features or may have only one or two clinical features. 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.

DIAGNOSIS/TESTING:

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. Molecular genetic testing can identify epigenetic and genomic alterations of chromosome 11p15 in individuals with BWS: Loss of methylation on the maternal chromosome at imprinting center 2 (IC2) in 50% of affected individuals; Paternal uniparental disomy for chromosome 11p15 in 20%; and Gain of methylation on the maternal chromosome at imprinting center 1 (IC1) in 5%. Methylation alterations associated with deletions or duplications in this region have high heritability. Sequence analysis of CDKN1C identifies a heterozygous maternally inherited pathogenic variant in approximately 40% of familial cases and 5%-10% of cases with no family history of BWS.

MANAGEMENT:

Treatment of manifestations: Treatment of hypoglycemia to reduce the risk of central nervous system complications; abdominal wall repair for omphalocele; endotracheal intubation for a compromised airway and use of specialized nipples or nasogastric tube feedings to manage feeding difficulties resulting from macroglossia. Children with macroglossia may benefit from tongue reduction surgery in infancy or early childhood and from speech therapy. Surgery may be performed during early puberty to equalize significant differences in leg length secondary to hemihyperplasia; craniofacial surgery may benefit individuals with facial hemihyperplasia. Neoplasias are treated using standard pediatric oncology protocols. Nephrocalcinosis and other renal findings should be assessed and treated by a pediatric nephrologist. Referral of children with structural GI tract anomalies to the relevant specialist; standard management for cardiac problems; standard interventions for children with developmental delay. Prevention of secondary complications: Prompt evaluation and standard treatment for suspected urinary tract infections to prevent secondary renal damage. Surveillance: Monitor for hypoglycemia, especially in the neonatal period; screen for embryonal tumors by abdominal ultrasound examination every three months until age eight years; monitor serum alpha-fetoprotein (AFP) concentration every two to three months in the first four years of life for early detection of hepatoblastoma. Annual renal ultrasound examination for affected individuals between age eight years and mid-adolescence to identify those with nephrocalcinosis or medullary sponge kidney disease; consideration of annual or biannual measurement of urinary calcium/creatinine ratio.

GENETIC COUNSELING:

Beckwith-Wiedemann syndrome is associated with abnormal regulation of gene transcription in two imprinted domains 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; approximately 15% have a family history consistent with parent-of-origin autosomal dominant transmission. Children of subfertile parents conceived by assisted reproductive technology (ART) may be at 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 in the general population that identifies findings suggestive of a diagnosis of BWS may lead to the consideration of chromosome analysis, chromosomal microarray, 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.

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