Beckwith-Wiedemann syndrome
Beckwith-Wiedemann syndrome (BWS) is a complex genetic disorder characterized by abnormal growth patterns, including increased body size and organ enlargement, along with a heightened risk for certain tumors. The syndrome is considered panethnic and is typically sporadic, occurring in approximately 1 in 13,700 live births, although familial instances can arise, often following an autosomal dominant inheritance pattern. Genetic abnormalities, particularly involving chromosome 11, play a crucial role in BWS, with defects in genes such as KCNQ1OT1 and CDKN1C contributing to its manifestations.
Common symptoms include macrosomia (large body size), macroglossia (enlarged tongue), visceromegaly (enlarged internal organs), and an increased risk of embryonal tumors like Wilms' tumor. Diagnosis is primarily clinical, supported by genetic testing to confirm the presence of specific molecular abnormalities. Treatment usually focuses on managing symptoms and includes surgical interventions for physical deformities, along with regular screening for tumors due to their aggressive nature. While prevention of BWS is not feasible, genetic counseling is recommended for affected families to understand recurrence risks and implications. Mortality rates vary, with significant risks present during infancy, particularly due to complications related to prematurity and cardiac issues.
Beckwith-Wiedemann syndrome
ALSO KNOWN AS: Exomphalos-macroglossia-gigantism syndrome; Wiedemann-Beckwith syndrome; BWS
DEFINITION: Beckwith-Wiedemann syndrome (BWS) is a complex genetic disorder affecting growth. Abnormalities associated with the disorder include enlarged body size, enlarged organs, and the presence of specific types of tumors. The etiology and inheritance of BWS are not well understood. The condition is thought to be sporadic in 85 percent of cases and inherited in an autosomal dominant manner in 15 percent of cases.
Risk Factors
Beckwith-Wiedemann syndrome (BWS) is panethnic and usually sporadic. However, in familial cases, family history may be a risk factor, especially those demonstrating autosomal dominant inheritance patterns. Chromosome abnormalities involving chromosome 11, such as translocations, inversions, or duplications, may increase the risk. Paternal uniparental (UPD) for chromosome 11 may also increase the risk.
Etiology and Genetics
Most cases of BWS are thought to involve abnormal expression or transcription of genes in the 11p15 region. The region is part of an imprinted domain; some genes are normally expressed only from the paternally derived alleles, while other genes in the region are expressed only from the maternally derived alleles. When there is a disruption, deletion, or mutation in one copy of the imprinted alleles, BWS occurs.
About 50 to 60 percent of cases of BWS are caused by defects in the KCNQ1OT1 gene in the 11p15 region. Methylation is a process in which a methyl group is added to a piece of DNA to inactivate the segment. When KCNQ1OT1 is not properly methylated, the genes cannot properly be regulated, which leads to the overgrowth and other features associated with BWS. Similarly, another 6 to 7 percent of cases of the disorder are caused by methylation defects in the H19 gene. The cases of BWS involving methylation defects are almost exclusively sporadic cases with a low recurrence risk.
Uniparental disomy (UPD) accounts for 10 to 20 percent of cases of BWS. This results in the loss of maternal alleles in the region and increased expression of paternal alleles in the region. The resulting underexpression and overexpression of involved genes results in the phenotype associated with BWS. Cases of UPD are usually a result of recombination events during mitosis. Since these events occur after conception, patients with UPD may be mosaic for the changes and are considered sporadic cases with low recurrence risks.
Mutations in the maternal allele of the CDKN1C gene account for 5 to 10 percent of sporadic cases and 40 percent of familial (autosomal dominant) cases of BWS. Chromosomal abnormalities, including maternal translocations involving chromosome 11, inversions of chromosome 11, or duplication of paternally derived 11p15, account for about 1 to 2 percent of BWS. Autosomal dominant cases have up to a 50 percent risk of recurrence, while chromosomal abnormalities vary in their recurrence risks. The remaining causes of BWS are not yet known.
Symptoms
The majority of symptoms related to BWS are related to overgrowth of various tissues. Prenatal overgrowth occurs in about 50 percent of cases and can be associated with prematurity. Also frequently seen is macrosomia (large body size), macroglossia (large tongue), and visceromegaly (large internal organs). Cardiomyopathy is also common. Children with BWS are at an increased risk for developing embryonal tumors, including Wilms’ tumor and hepatoblastoma. As one 2024 study published in the British Journal of Cancer illustrated, this is particularly true of Wilms' tumor because that condition exhibits the same structural and epigenetic changes at chromosome 11p15 that also cause BWS. Renal abnormalities are found in about 50 percent of cases. Omphalocele, an abdominal wall defect, can also be seen in association with BWS. There are significant risks of mortality, mostly as a result of complications of prematurity. Hemihyperplasia may be seen, resulting in unbalanced growth of body segments or specific tissues; this may resolve over time. The growth rate usually slows in late childhood. Developmental delay is not common unless there is a chromosome abnormality present.
Screening and Diagnosis
BWS occurs in approximately 1 in 13,700 live births in developed countries worldwide. A precise rate of occurrence is difficult to determine, as those with mild or atypical symptoms may never be diagnosed. Several studies have shown incidence rates to be higher in cases of assisted reproduction.
Diagnosis is typically achieved through clinical symptoms. Genetic studies for suspected diagnoses should be offered for confirmation. Molecular studies for diagnosis include methylation studies, karyotyping with fluorescence in situ (FISH), microsatellite analysis, and sequencing of the CDKN1C gene. Prenatal testing is available by chorionic villus sampling or amniocentesis when the molecular abnormality has been previously identified in the family.
Treatment and Therapy
Treatment of BWS involves management of presenting symptoms, which may include surgery to correct the physical consequences of omphalocele, hemihyperplasia, macroglossia, and renal malformations. Periodic screening for embryonal tumors is essential because of their fast-growing and potentially dangerous nature. Speech therapy, physical therapy, and occupational therapy may be helpful in overcoming obstacles associated with macroglossia and hemihyperplasia.
Prevention and Outcomes
Except for the familial cases where prenatal diagnosis can be performed, prevention of BWS is not possible. Genetic counseling should be offered to all families with a person confirmed or suspected to be affected with BWS. About 20 percent of infants with BWS die as a result of prematurity and cardiac complications. Beyond infancy, mortality rates depend on the presence of symptoms and appropriate management.
Bibliography
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