Beckwith-Wiedemann syndrome – risk management

Beckwith-Wiedemann syndrome (BWS) is a multisystem imprinting disorder variably characterised by overgrowth and an increased risk of embryonal tumours during early childhood (e.g. Wilms tumour, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma). It is caused by epigenetic/genomic alterations leading to abnormal methylation at chromosome 11p15.5 or a pathogenic variant in the CDKN1C gene.^r

This risk management guideline has been developed for individuals with a clinical and/or genetic diagnosis of Beckwith-Wiedemann syndrome who have NOT been diagnosed with a relevant cancer/tumour. 

The care of individuals affected with a relevant cancer/tumour should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-­treatment follow up.

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised. 

• Individuals with a clinical and/or genetic diagnosis of Beckwith-Wiedemann syndrome.
• Individuals with isolated hemihyperplasia who also have a Beckwith-Wiedemann syndrome-related genomic defect.

Exclusion criteria

• Individuals without a clinical and/or genetic diagnosis of Beckwith-Wiedemann syndrome.
• Individuals with isolated hemihyperplasia without a Beckwith-Wiedemann syndrome-related genomic defect.

Abbreviations: UPD11(pat) - paternal uniparental disomy of chromosome 11, IC2 LOM - imprinting centre 2 loss of methylation, IC1 GOM - imprinting centre 1 gain of methylation 

*Higher rates of cancer diagnosis have been reported in a research study where recruitment criteria included the presence of embryonal tumours.^r However these higher rates are unlikely to be applicable to the general Beckwith-Wiedemann syndrome patient population.

 The choice of risk management strategy should take into account current age, other health issues and residual cancer risk.

Abbreviations: UPD11(pat) - paternal uniparental disomy of chromosome 11, IC2 LOM -  imprinting centre 2 loss of methylation, IC1 GOM - imprinting centre 1 gain of methylation 

* including but not limited to: abdominal distension/pain/mass, haematuria, hypertension, and prompt reporting of unusual symptoms

**The impact of lifestyle on general cancer risks should be discussed e.g. exercise regularly, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure

Children with Beckwith-Wiedemann syndrome (BWS) are at increased risk for mortality associated with neoplasia, particularly Wilms tumour and hepatoblastoma, but also neuroblastoma, adrenocortical carcinoma, and rhabdomyosarcoma. Some literature reports propose tumour surveillance guidelines based on the molecular alteration detected^rrr whereas others have highlighted the challenges in definitively assigning tumour risk based on molecular classification in BWS.^rr The overall estimated risk for tumour development in children with BWS is around 8%,^r and the increased risk is concentrated in the first 7 years of life.^r Tumour development in affected individuals older than age 7 years is rare, and there is currently little evidence to suggest adults with BWS are at increased cancer risk, although this remains under investigation.^r Screening is indicated for Wilms tumour and hepatoblastoma due to their high incidence in BWS, and that survival of both tumours is closely related to the clinical stage at the time of diagnosis and the ability to resect the tumour. Abdominal ultrasound is the preferred modality as it is simple, tolerated, and cost-effective for Wilms tumour and hepatoblastoma surveillance.^r

Wilms tumour

The median age of identification of Wilms tumour is around 2 years.^r Children with BWS and Wilms tumour, when compared with non-syndromic children with Wilms tumour, present with less metastatic disease because of earlier stage disease, fewer anaplastic tumours and a higher incidence of bilateral synchronous or metachronous recurrence.^r Although patients with BWS and Wilms tumour who are diagnosed using abdominal ultrasound surveillance have a smaller tumour size than children with sporadic Wilms tumour, overall survival values are similar (at least 90% at 4 years).^r A scan interval of 3–4 months is recommended, as interval tumours have been reported with scan intervals in excess of 4–6 months, and the rapid Wilms tumour growth rate (estimated doubling time 11-40 days).^r Screening with serial abdominal ultrasounds up to age 7 years is effective in detecting 95% of all Wilms tumours.^r

Hepatoblastoma

Around 90% of hepatoblastomas occur before the age of 4 years, with a median age of 16 months.^r There is lack of evidence for earlier stage at diagnosis and/or better prognosis in children who have hepatoblastoma surveillance versus children who present clinically. When surveillance is offered abdominal ultrasound is the preferred modality, and most published surveillance guidelines recommend 3 monthly ultrasound until the age of 4 years.^r 

Some experts suggest combining ultrasound with alpha-fetoprotein (AFP) measurements, as AFP is secreted in >95% of hepatoblastomas and a rising trend is likely to indicate hepatoblastoma development.^r However, in the paediatric setting, interpreting serum AFP levels is complicated by the wide normal range and variability in concentrations in early infancy. In view of the burden of repeated venepuncture and the complexity of interpreting elevated AFP levels, it has been debated whether the potential benefits of AFP measurements outweigh the drawbacks.^rrrr The international consensus group do not recommend AFP measurements as there is no evidence of benefit.^r

Neuroblastoma

Although reported in all BWS molecular subgroups, neuroblastomas are preferentially associated with CDKN1C pathogenic variants, with a frequency of ~4%.^r Surveillance for neuroblastomas with urinary vanillylmandelic acid and homovanillic acid and/or the catecholamine:creatinine ratio, combined with three monthly abdominal ultrasounds until age 2 years has been suggested.^r However, previous neuroblastoma surveillance strategies using urinary markers in large-scale population infant settings had a very minor influence on the related morbidity and mortality,^r and there is currently no evidence that neuroblastoma surveillance in BWS improves treatment and survival.

Expert advice about sibling and offspring recurrence risk should be sought from a clinical genetics service or familial cancer centre, as the risk will vary by molecular mechanism.

Informing family members about hereditary cancer.

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