Definition

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.

Key Data

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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)
Function Complex
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
Genotype-
phenotype
correlation		 Close correlation for all clinical symptoms present, risk of cancer up to the age of 7. Birthday:

  • IC2 hypomethylation 2.6% (especially hepatoblastomas)
  • IC1 hypermethylation 28.1% (especially nephroblastoma)
  • Uniparenteral disomy 16% (especially nephroblastoma)
  • CDKN1C mutation 6.9% (especially neuroblastoma)
Penetrance
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Diagnosis

The Beckwith-Wiedemann Syndrome Spectrum (BWSp) includes:

  • Patients with clinically diagnosed BWS and evidence of molecular genetic change in 11p15

  • Patients with clinically diagnosed (≥ 4 points of diagnostic criteria) BWS without proven molecular genetic changes

  • Patients with atypical clinical symptoms and known molecular genetic changes in 11p15

  • Patients with lateralised overgrowth (LO) if they also show a known molecular genetic change in 11p15.

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)

  • Macroglossia

  • Omphalocele

  • Lateralised large growth

  • Multifocal/bilateral Wilms Tumors or nephroblastomatosis

  • Hyperinsulinism (if postnatal hypoglycemia (blood glucose levels <50 mg/dl in the first 6 hours of life and <60 mg/dl afterwards) persists for longer than 1 week and/or requires intensified treatment)

  • Adrenocortical cytomegaly, mesenchymal planetary dysplasia, pancreatic adenomatosis

Secondary Criteria (1 point per symptom)

  • Birth weight > + 2sd

  • Facial nevus flammeus

  • Polyhydramnion/Placentomegaly

  • Ear folds/ear pits

  • Transient hypoglycemia/hyperinsulinism

  • Typical BWS tumors (neuroblastoma, rhabdomyosarcoma, unilateral Wilms tumor, hepatoblastoma, adrenocortical carcinoma, pheochromocytoma)

  • Nephromegaly/hepatomegaly

  • Umbilical hernia/rectus diastasis

Genetic Diagnostics

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:

  • Detection of hypomethylation of maternal IC2 in 50% of cases

  • Hypermethylation of maternal IC1 in 5-10% of cases

  • Paternal uniparental disomy in 20% of cases

  • Point mutations in CDKN1C in 5% of cases

  • Chromosomal changes in <5% of cases

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.

Differential Diagnoses

  • Simpson-Golabi-Behmel syndrome (large growth syndrome with organomegaly, abdominal wall defects and macroglossia)

  • Perlman syndrome (prenatal gross growth, hyperinsulinism, risk for Wilms Tumor)

  • Costello syndrome (macrosomia at birth, polyhydramnion)

Clinical Presentation

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.

Therapeutic Considerations

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.

Surveillance Recommendations

Surveillance Recommendations

Embryonal Tumors

  • Depends on genotype

  • Abdomen sonography every 3 months up to the age of 7 for all children with BWS, except for children with IC2 hypomethylation

  • Early detection is not recommended for children with IC2 hypomethylation.

  • No routine screening of the α-fetoprotein

  • No routine screening of urinary catecholamines

  • Early, low-threshold Diagnosis is recommended for any clinical symptoms that may be tumor-associated or for parental care.

  • The oncological therapy in BWSp can deviate from the standard regime and should be coordinated with the respective study management.

Body Growth and Lateralised Large Growth

  • Annual measurement of body size until completion of size growth, if necessary treatment of high growth by pediatric endocrinologists

  • Annual examination of leg lengths until completion of size growth, with difference in leg length consultation of a pediatric orthopedist (shoe elevation with difference up to 2 cm, epiphysiodesis with difference >2 cm)

  • Usually no treatment for length differences of the upper extremity

Macroglossia

  • In the case of obstruction of the respiratory tract, a detailed diagnosis including polysomnography and pulmological examination should be carried out.

  • In case of difficulties in eating or speaking, persistent hypersalivation, malpositioned teeth or psychosocial problems, tongue reduction surgery may be considered after the first year of life.

Abdominal Wall Defects

  • Treatment according to usual standard, no specific recommendation for BWS

Hypoglycemia

  • Monitoring of postnatal blood glucose levels for 48 hours, in the case of hypoglycemia, monitoring in a neonatal intensive care unit if necessary

  • Diagnostic fast test (measurement of glucose, insulin, ketones after 6 hours (4 hours for premature babies) sobriety)

  • Treatment of hypoglycemia/ hyperinsulinism according to usual standards

Cardiac Malformations

  • Cardiopulmonary examination for diagnosis, clinical abnormalities consultation of a pediatric cardiologist for echocardiography

  • For malformations treatment according to usual standard

Neurological Development

  • Regular study of cognitive progress (risk factors for delayed neurological development associated with BWS are postnatal hypoglycemia, preterm birth and carriers of chromosomal rearrangements)

  • In case of neurological symptoms, an MRI of the skull should be performed.

Renal Complications

  • Screening for renal or urological malformations by clinical examination and sonography at diagnosis, in case of abnormalities child nephrological presentation and treatment according to usual standard

  • Re-examination (clinical examination, measurement of blood pressure and sonography) during transition

Late Effects

  • At the time of transition (16-18 years), symptoms/complications requiring control should be recorded again to ensure follow-up.

  • Adolescents should be advised of the possibility of genetic counseling prior to family planning.

Psychosocial Aspects

  • Psychosocial support should be offered on a low-threshold basis.

  • If possible, contact with a support group or affected families should be offered when a diagnosis is made.