Beckwith-Wiedemann syndrome

General Information (adopted from Orphanet):

Synonyms, Signs: BWS
Wiedemann-beckwith syndrome
BWCR, included
WBS Beckwith-Wiedemann syndrome chromosome region, included
Exomphalos-macroglossia-gigantism syndrome
EMG syndrome
Exomphalos - macroglossia - gigantism
Number of Symptoms 0
OrphanetNr: 116
OMIM Id: 130650
ICD-10: Q87.3
UMLs: C0004903
MeSH: D001506
MedDRA: 10050344
Snomed: 81780002

Prevalence, inheritance and age of onset:

Prevalence: 9.5 of 100 000 - PMID: 25898929 [IBIS]
Age of onset: Antenatal
- PMID: 25898929 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Inherited renal cell cancer-predisposing syndrome
 -Rare genetic disease
 -Rare oncologic disease
 -Rare renal disease
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare maxillo-facial surgical disease
Overgrowth syndrome
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
Polymalformative genetic syndrome with increased risk of developing cancer
 -Rare genetic disease
 -Rare oncologic disease
Syndrome associated with hypertrophic cardiomyopathy
 -Rare cardiac disease
 -Rare genetic disease
Syndrome or malformation associated with head and neck malformations
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare maxillo-facial surgical disease
 -Rare otorhinolaryngologic disease
Syndromic renal or urinary tract malformation
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare renal disease


This term does not characterize a disease but a group of diseases. Annotations can be found at a more specific level. Beckwith-Wiedemann syndrome comprises the following entries: Phenodis:2518 Beckwith-Wiedemann syndrome due to imprinting defect of 11p15; Orphanet:231117; Phenodis:2519 Beckwith-Wiedemann syndrome due to CDKN1C mutation; Orphanet:231120; Phenodis:2520 Beckwith-Wiedemann syndrome due to 11p15 microdeletion; Orphanet:231127; Phenodis:2521 Beckwith-Wiedemann syndrome due to 11p15 translocation/inversion; Orphanet:231130; Phenodis:2651 Beckwith-Wiedemann syndrome due to NSD1 mutation; Orphanet:238613; Phenodis:7603 Beckwith-Wiedemann syndrome due to 11p15 microduplication; Orphanet:96076; Phenodis:7657 Beckwith-Wiedemann syndrome due to paternal uniparental disomy of chromosome 11; Orphanet:96193; Genetically, Beckwith-Wiedemann syndrome (BWS) is caused by genetic and epigenetic alterations affecting the imprinted growth-regulatory genes located on chromosome 11p15. Approximately 50% of all cases result from methylation alterations in imprinting control regions 1 and 2 (known as KvDMR1, a locus that regulates expression of multiple genes) in chromosome 11, which lead to impaired imprinting of genes IGF2, H19, CDKN1C and KCNQ1OT1. About 20% of BWS cases are found to have mosaic paternal uniparental disomy (UPD) of chromosome 11p15, hence they have increased expression of the paternally expressed growth promoter IGF2 and reduced expression of the maternally expressed CDKN1C and H19 genes. In about 5% of patients, BWS can be caused by mutations in the CDKN1C gene, and even less common (1–2%) are chromosomal abnormalities such as translocation or duplication of the genetic material from chromosome 11p15.5 (PMID:26863215). Genetic and epigenetic anomalies are found in approximately 75% of patients, consisting of the disruption of expression of two imprinted loci on the 11p15.5 chromosomal region: imprinting center 1 (IC1), which regulates the physiological monoallelic expression of the insulin growth factor 2 gene (IGF2) and the tumor suppressor gene H19, and imprinting center 2 (IC2), which mainly regulates the expression of the cyclin-dependent kinase inhibitor 1C gene (CDKN1C). Both imprinting centers are differentially methylated on the paternal and maternal allele in order that only one allele, parent-specific for each imprinted gene, is expressed. The complex regulation may be disrupted by numerous genomic, genetic, and epigenetic mechanisms: 1. Loss of methylation (LOM) of IC2 on the maternal chromosome, the most frequent defect causing approximately 50% of BWS 2. Gain of methylation (GOM) at IC1 on the maternal chromosome, 5–10% of cases 3. Both LOM-IC2 plus GOM-IC1 caused by paternal mosaic uniparental disomy for chromosome 11p15 (UPD), accounting for 20% of cases 4. Mutations in CDKN1C gene causing inheritable BWS, observed in 10% of patients 5. Rare chromosomal rearrangements including duplications, deletions, inversions, or translocations involving these imprinted regions, accounting for 1–2% of cases overall (PMID:22015620). Beckwith–Wiedemann syndrome (BWS) is the commonest congenital overgrowth condition (1:10,500 live births) and represents a paradigmatic genetic imprinting disorder and cancer predisposition syndrome. Its clinical features include neonatal macrosomia, postnatal overgrowth, abdominal wall defects, macroglossia, ear anomalies, naevus flammeus, hemihyperplasia, organomegaly, nephroureteral malformations, hypoglycaemia, and predisposition to develop embryonic tumors in infancy). These features variably combine with different severity degrees depicting a broad phenotypic spectrum. Mild phenotypes can easily be mistaken for variants of normal subjects. Moreover, phenotype can change over time: many cases mitigate their expression during early childhood, and, vice versa, features not present at birth can appear in childhood. The diagnosis is clinical, based on criteria revised over time. The molecular tests have a confirmatory and prognostic role, but cannot exclude the disease if negative. Positive family history is associated with CDKN1C mutations, IC1 deletions/mutations, and IC2 duplication/deletions. CKDN1C mutations account for 50% of familial cases and 5% of those with negative family history. NLPR2 mutations, although anecdotal, should be considered in genetic counseling (PMID:25898929).

Symptom Information: Sort by abundance 

Associated genes:


ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference
CDKN1C rs104894200 pathogenic RCV000009290.2
CDKN1C rs137852766 pathogenic RCV000009287.2
CDKN1C rs267606716 pathogenic RCV000009291.2
CDKN1C rs267606716 pathogenic RCV000009292.2
CDKN1C rs387906399 pathogenic RCV000009289.3
CDKN1C rs587777866 pathogenic RCV000172924.1
CDKN1C rs772704243 pathogenic RCV000172988.1
CDKN1C rs786205234 pathogenic RCV000172982.1
CDKN1C rs786205235 pathogenic RCV000172989.1
CDKN1C rs786205236 pathogenic RCV000172990.1
CDKN1C rs786205237 pathogenic RCV000172986.1
CDKN1C rs786205238 pathogenic RCV000172983.1
CDKN1C rs786205239 pathogenic RCV000172985.1
CDKN1C rs786205240 pathogenic RCV000172987.1
CDKN1C rs786205241 pathogenic RCV000172984.1
CDKN1C rs797045445 pathogenic RCV000192927.1

Additional Information:

Description: (OMIM) Beckwith-Wiedemann syndrome is a pediatric overgrowth disorder involving a predisposition to tumor development. The clinical presentation is highly variable; some cases lack the hallmark features of exomphalos, macroglossia, and gigantism as originally described by Beckwith (1969) and Wiedemann ...
Diagnosis OMIM Diagnosis is based on clinical findings. A 'mild' presentation may include prominent tongue and umbilical hernia (Weksberg et al., 2010). A careful cytogenetic analysis of the 11p15 region is recommended. Prenatal diagnosis by ultrasonography is possible (Nivelon-Chevallier et ...
Clinical Description OMIM Individuals with BWS may grow at an increased rate during the latter half of pregnancy and in the first few years of life, but adult heights are generally in the normal range. Abnormal growth may also manifest as ...
Molecular genetics OMIM Jeanpierre et al. (1985) found no obligate or consistent duplication of any 11p markers in BWS and concluded that duplication of INS (176730), HRAS1 (190020), and IGF2 (147470) cannot be directly responsible for the hyperinsulinism, predisposition to neoplasm, ...
Population genetics OMIM Thorburn et al. (1970) described 6 cases in Jamaican blacks and estimated a population incidence of 1 in 13,700 births. Weksberg et al. (2010) noted that this figure is likely an underestimate as milder phenotypes may not be ...
Diagnosis GeneReviews No consensus diagnostic criteria for Beckwith-Wiedemann syndrome (BWS) exist, although the presence of several findings (e.g., three major or two major and one minor) is often used to confer a clinical or provisional diagnosis. In general, major findings are those associated with BWS and uncommon in the general population whereas minor findings are those associated with BWS but common in the general population. ...
Clinical Description GeneReviews Incidence figures for the specific individual clinical findings in Beckwith-Wiedemann syndrome (BWS) vary widely in published reports. The following features, however, are clearly part of the phenotype....
Genotype-Phenotype Correlations GeneReviews Phenotype-genotype correlations have been reported as follows:...
Differential Diagnosis GeneReviews Overgrowth. Beckwith-Wiedemann syndrome (BWS) is often considered in the differential diagnosis of children presenting with overgrowth. It is important to note the existence of as-yet unclassified overgrowth syndromes that need to be differentiated from BWS. In children considered to have BWS and developmental delay who have a normal chromosome study and no history of hypoxia or hypoglycemia, other causes for developmental delay need to be considered. If structural or cardiac conduction defects are present, the differential diagnosis should include Simpson-Golabi-Behmel syndrome and Costello syndrome. ...
Management GeneReviews To establish the extent of disease in an individual diagnosed with Beckwith-Wiedemann syndrome (BWS), the following evaluations are recommended: ...
Molecular genetics GeneReviews Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....