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:

Overview of the Chapters on This Page:

  • Clinical Presentation

  • Special Features of Treatment

  • Recommendations for Early Detection in Your Patients
  • Further Information (e.g., Links to Support Groups)

  • Clinical Presentation

  • Special Features of Treatment

  • Recommendations for Early Detection in Your Patients
  • Further Information (e.g., Links to Support Groups)

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 CDKN1C mutation, 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

Embryonic Tumors

Based on the genetic makeup, the following recommendations apply to children with BWS:

  • Children with BWS should receive abdominal ultrasonography every 3 months until the age of 7, except for those with IC2 hypomethylation.
  • No screening tests are advised for children with IC2 hypomethylation.
  • There is no need for routine screening of α-fetoprotein or urinary catecholamines.
  • It is recommended to promptly diagnose any clinical symptoms that may be related to tumors or in cases of parental concern.
  • If oncological therapy is required for BWSp, it may differ from the standard regimen and should be coordinated with the respective study management.

Body Growth and Lateralized Tall Stature

  • Annual measurement of height until completion of height growth, treatment of tall stature by pediatric endocrinologist if necessary
  • Annual examination of leg lengths until completion of height growth, consultation with a pediatric orthopedist if there is a difference in leg length (shoe elevation for differences up to 2 cm, epiphysiodesis for differences >2 cm)
  • Usually, no treatment for upper limb length differences

Abdominal Wall Defects

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

Hypoglycaemia

  • Monitoring of postnatal blood glucose levels for 48 hours, in case of hypoglycemia monitoring in a neonatal intensive care unit if necessary
  • Diagnostic fasting test (measurement of glucose, insulin, and ketones after 6 hours (4 hours for premature babies) of fasting)
  • Treatment of hypoglycemia/hyperinsulinism according to the usual standard

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 case of vitia

Neurological Development

  • Regular examination of cognitive progress (risk factors for delayed neurological development associated with BWS are postnatal hypoglycemia, prematurity, and carriers of chromosomal rearrangements)
  • An MRI of the skull should be performed in case of neurological symptoms.

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, measurement of blood pressure, and sonography) at transition

Late Effects

  • During transition (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 counseling before family planning.

Psychosocial Aspects

  • Psychosocial support should be offered at a low threshold.
  • When a diagnosis is made, contact with a self-help group or affected families should be offered if possible.