Beckwith-Wiedemann syndrome (BWS; OMIM #130650) is a multisystemic disease characterised by variable characteristics such as macroglosssia, pre- and postnatal macrosomia, unilateral lateralised proliferation, neonatal hypoglycaemia, and an increased risk of childhood cancer, particularly nephroblastoma, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma.
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|Synonyms||Exomphalos macroglossia-gigantism syndrome (EMG)
Wiedemann-Beckwith syndrome (WBS)
|Genes||Complex epigenetic and intragenetic changes of parental imprinted genes on the short arm of chromosome 11(15.5-11p15.4).|
|Gene products||IGF2 (growth factor), H19 (long non-coding RNA), CDKN1C (cell cycle inhibitor), KCNQ1OT1 (long non-coding RNA)|
|Heredity||Risk of recurrence and inheritance variable and dependent on the molecular genetic change 10-15%
familial (especially CDKN1C mutations), autosomal dominant, here dependent on the sex of the inheriting parent, with non-familial occurrence overall low risk of recurrence
|Prevalence||About 1:10.340 live births|
|Close correlation for all clinical symptoms present, risk of cancer up to the age of 7. Birthday:
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The Beckwith-Wiedemann Syndrome Spectrum (BWSp) includes:
Clinical Diagnostic Criteria
The diagnosis can be made clinically on the basis of main and secondary criteria.
At ≥ 4 points is clinically a classical BWS available, at ≥ 2 points should be genetic diagnostics. The main criteria lead to the diagnosis, the secondary criteria make them more probable.
Main Criteria (2 points per symptom)
Secondary Criteria (1 point per symptom)
The chromosome region on the short arm of chromosome 11 (15.5-11p15.4) contains two functionally independent domains with their own imprinting control region (H19/IGF2:IG DMR = IC1 and KCNQ1OT1:TSS DMR = IC2), whose gene expression is altered by disturbed DNA methylation (hyper- and hypomethylation), paternal uniparental disomy and point mutations. Known changes are detectable in 80% of patients:
For genetic diagnosis, the methylation pattern of IC2 and IC1 and the copy number variation (CNV) should first be determined using methylation-sensitive multiplex ligation probe analysis (MS-MLPA). IC2 hypomethylation, IC1 hypermethylation and uniparental paternal disomy (upd(11)pat) are already diagnosed. In the case of inconspicuous findings in MS-MLPA, a CDKN1C mutation, an undetectable mosaic, a rare balanced chromosomal rearrangement or a previously unknown cause for BWS (up to 20%) may be present.
The BWS presents itself in childhood with variably pronounced phenotype of the above mentioned clinical characteristics.
In particular, macroglossia (present at 85%) and hypoglycemia with a high need for glucose substitution (present at approx. 50%) allow a clinical diagnosis to be made already during the neonatal period. Apart from additional symptoms and complications (premature birth, abdominal wall defects, hyperinsulinism that is difficult to treat), the newborns usually develop in a regular and neurologically inconspicuous manner. A neurocognitive developmental delay may occur after severe neonatal hypoglycemia or chromosomal rearrangement. Macroglossia can cause additional difficulties due to feeding difficulties, airway obstruction and persistent hypersalivation, and about 40% of children have a surgical reduction of the tongue.
Up to the age of 7, children with BWSp have a much higher risk of cancer, depending on the genotype, so that close control examinations (see below) are recommended. Before puberty, the tumor risk is similar to that of the normal population. In adulthood the clinical symptoms are often very discreet or no longer identifiable.
The clinical symptoms of patients with BWS affect a variety of different medical disciplines (neonatology, oral and maxillofacial surgery, pediatric orthopedics, pediatric oncology) and require interdisciplinary care and treatment.
The close epi-/genotype/phenotype correlation, especially with regard to tumor risk, enables individual and targeted prevention.