Beckwith-Wiedemann Syndrome Spectrum – Definition
Beckwith-Wiedemann syndrome (BWS; OMIM #130650) is a multisystem disorder characterized by variable features such as macroglossia, pre-and postnatal macrosomia, unilateral lateralized tall stature, neonatal hypoglycemia, and an increased risk of childhood cancer, particularly nephroblastoma, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma.
Synonyms:
Exomphalos-macroglossia-gigangism syndrome (EMG)
Wiedemann-Beckwith syndrome (WBS)
Gene:
Complex epigenetic and intragenetic alterations 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
Inheritance:
Risk of recurrence and inheritance variable and dependent on the molecular genetic change
10-15% familial (mainly CDKN1C mutations), autosomal dominant, here depending on the sex of the inheriting parent, overall low risk of recurrence in non-familial cases
Prevalence:
about 1:10,340 live births
Genotype-phenotype correlation:
Close correlation for all clinical symptoms, cancer risk up to the age of 7:
- IC2 hypomethylation 2.6% (mainly hepatoblastomas)
- IC1 hypermethylation 28.1% (mainly nephroblastomas)
- Uniparental disomy 16% (mainly nephroblastomas)
- CDKN1C mutation 6.9% (mainly neuroblastomas)
Penetrance:
–
Beckwith-Wiedemann Syndrome Spectrum – Diagnosis
The Beckwith-Wiedemann syndrome spectrum (BWSp) includes
- Patients with clinically diagnosed BWS and evidence of a molecular genetic alteration in 11p15
- Patients with clinically diagnosed (≥ 4 points of the diagnostic criteria) BWS without detected molecular genetic alterations
- Patients with atypical clinical symptoms and known molecular genetic alteration in 11p15
- Patients with unilateral tall stature (lateralized overgrowth = LO) also have a known molecular genetic alteration in 11p15.
Clinical Diagnosis
The diagnosis can be made clinically based on main and secondary criteria.
If ≥ 4 points, a classic BWS is clinically present; if ≥ 2 points, a genetic diagnosis should be made. The main criteria lead to the diagnosis; the secondary criteria make it more probable.
Main Criteria (2 Points per Symptom)
- Macroglossia
- Omphalocele
- Lateralized tall stature
- Multifocal/bilateral Wilms tumors or nephroblastomatosis
- Hyperinsulinism (if postnatal hypoglycemia (blood glucose level <50 mg/dl in the first 6 hours of life and <60 mg/dl thereafter) persists for more than 1 week and/or requires intensified treatment)
- Adrenocortical cytomegalovirus, mesenchymal pancreatic dysplasia, pancreatic adenomatosis
Secondary Criteria (1 Point per Symptom)
- Birth weight > + 2SD
- Facial nevus flammeus
- Polyhydramnios/placentomegaly
- Ear folds/ear dimples
- Transient hypoglycemia/hyperinsulinism
- Typical BWS tumors (neuroblastoma, rhabdomyosarcoma, unilateral Wilms tumor, hepatoblastoma, adrenocortical carcinoma, pheochromocytoma)
- Nephromegaly/hepatomegaly
- Umbilical hernia/rectus diastasis
Genetic Diagnostics
The chromosomal region on the short arm of chromosome 11 (15.5-11p15.4) harbors two functionally independent domains with their imprinting control region (H19/IGF2:IG DMR = IC1 and KCNQ1OT1:TSS DMR = IC2), whose gene expression is altered by impaired DNA methylation (hyper- and hypomethylation), paternal uniparental disomy and point mutations. Known changes are detectable in 80% of patients:
- Detection of hypomethylation of the 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, usually using methylation-sensitive multiplex ligation probe analysis (MS-MLPA). IC2 hypomethylation, IC1 hypermethylation, and uniparental paternal disomy (up (11)pat) are already diagnosed in this way. In the case of unremarkable findings in the MS-MLPA, a pathogenic variant in CDKN1C, an undetectable mosaic, a rare balanced chromosomal rearrangement or a previously unknown cause of BWS (up to 20%) could be present.
Differential Diagnoses
- Simpson-Golabi-Behmel syndrome (tall stature syndrome with organomegaly, abdominal wall defects, and macroglossia)
- Perlman syndrome (prenatal tall stature, hyperinsulinism, risk of Wilms tumor)
- Costello syndrome (macrosomia at birth, polyhydramnios)
Clinical Presentation
BWS presents in childhood with a variable phenotype of the above-mentioned clinical characteristics.
In particular, macroglossia (present in 85%) and hypoglycemia with a high need for glucose substitution (present in approx. 50%) mean that a clinical diagnosis is sometimes already made in the neonatal period. Apart from additional symptoms and complications (prematurity, abdominal wall defects, difficult-to-treat hyperinsulinism), the newborns usually develop normally and without neurological abnormalities. 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 approximately 40% of children undergo surgical tongue reduction.
Up to the age of 7, children with BWSp have a much higher risk of cancer, depending on the genotype, so close monitoring (see below) is recommended. Before puberty, the tumor risk is similar to that of the normal population. In adulthood, the clinical symptoms are often very discrete or no longer identifiable.
Special Features of Treatment
The clinical symptoms of patients with BWS involve various medical disciplines (neonatology, oral and maxillofacial surgery, pediatric orthopedics, pediatric oncology) and require interdisciplinary care and treatment.
The close epi-/genotype-phenotype correlation, particularly about tumor risk, enables individual and targeted prevention.
Diagnosis of Beckwith-Wiedemann Syndrome Spectrum- What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnosis of Beckwith-Wiedemann Syndrome Spectrum - What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Recommendations for Early Detection in Your Patients
Tumour screening for patients with IC1-GOM, IC2-LOM, pUPD
- Wilms’ tumour: Sonography of the kidneys every 3 months from birth until the child’s 7th birthday
- Especially with pUPD: look at the adrenal glands!
- For patients with IC2-LOM, the AACR recommends the above Wilms’ tumour screening; the European recommendations do not recommend screening for Wilms’ tumour. In these cases, screening should be considered on an individual basis.
- Hepatoblastoma: Abdominal ultrasound + AFP every 3 months from birth to 3rd birthday
CAVE: Use BWS-specific reference values, as AFP levels are higher in BWS patients! - Physical examination every 6 months
Tumour screening for patients with a pathogenic CDKN1C variant
- No screening for Wilms’ tumour and hepatoblastoma
- Screening for neuroblastoma:
- 0-6 years: abdominal ultrasound, vanillic mandelic acid and homovanillic acid in urine every 3 months, chest x-ray every 6 months
- 6-10 years: abdominal ultrasound, vanillic mandelic acid and homovanillic acid in urine every 6 months, chest x-ray every 6-12 months
- >10 years: No screening recommended
Body growth and lateralised height
- Annual height measurement until height growth is complete, treatment for tall stature by paediatric endocrinologist if needed
- Annual assessment of leg length until height growth is complete, consultation with a paediatric orthopaedic surgeon if there is a difference in leg length (shoe lift if difference up to 2 cm, epiphysiodesis if difference >2 cm).
- Usually no treatment for upper limb length differences
Macroglossia
- Airway obstruction: diagnostics including polysomnography and pulmonological examination
- Tongue reduction surgery may be considered after the first year of life in cases of difficulty eating or speaking, persistent hypersalivation, malocclusion or psychosocial problems
Abdominal Wall Defects
- Treat as usual, no specific recommendation for BWS
Hypoglycaemia
- Postnatal blood glucose monitoring for 48 hours, with neonatal intensive care monitoring for hypoglycaemia if required
- Diagnostic fasting test (measurement of glucose, insulin, and ketones after 6 hours (4 hours for premature infants) of fasting)
- Treatment of hypoglycaemia/hyperinsulinism according to usual standards
Cardiac Malformations
- Cardiopulmonary examination at the time of diagnosis, consultation with a pediatric cardiologist for echocardiography in case of clinical abnormalities
- Treatment according to the usual standard in the case of Vitia
Neurological Development
- Regular assessment of cognitive development (risk factors for delayed neurological development associated with BWS include postnatal hypoglycaemia, prematurity and carriers of chromosomal rearrangements)
- In the event of neurological symptoms, an MRI scan of the skull should be carried out
Renal Complications
- Screening for renal or urological malformations by clinical examination and sonography at the time of diagnosis; in the event of abnormalities, pediatric nephrological presentation and treatment according to the usual standard
- Repeated detailed examination (clinical examination, blood pressure measurement and sonography) at transition
Late Effects
- During the transition period (16-18 years), symptoms/complications requiring monitoring should be recorded again to ensure follow-up
- Adolescents should be made aware of the possibility of genetic counselling before family planning
Psychosocial Aspects
- Psychosocial support should be offered at a low threshold
- When a diagnosis is made, contact with a support group or affected families should be offered if possible.
