Overview 

Beckwith-Wiedemann syndrome (BWS) is the most prevalent illness associated with overgrowth and cancer susceptibility.¹ BWS occurs in approximately 1 in 10,000 births, however, this number may be underestimated, as children with milder forms of the condition might not receive a formal diagnosis or the 11p overgrowth spectrum.² 

Named after the doctors who first described it, Drs. Bruce Beckwith and Hans-Rudolf Wiedemann, BWS is characterised by a range of physical anomalies and an increased risk of certain malignancies. Despite its rarity, BWS is a notable example of the complex interplay between genetics and human development.⁷ There is no apparent racial or gender preference and it is most commonly diagnosed in early childhood, as it is a congenital condition. Children with BWS have a higher risk of developing embryonal malignancies, such as hepatoblastoma and Wilms' tumour, typically before the ages of four and seven, respectively. As individuals with BWS age, the clinical characteristics of the condition often worsen.³

Clinical presentation - symptoms and characteristics

When a child is born with multiple symptoms of BWS, the condition is usually diagnosed at birth. The severity of the disorder can vary widely among children, and not all will display every symptom. Some individuals may present with only a single, minor characteristic, such as isolated limb hemihypertrophy (also known as hemi-hyperplasia).² Others will show a combination of certain characteristics. Some of these are:^{3, 4}

• Placentomegaly (abnormally increased placenta thickness) and/or polyhydramnios (when you have too much amniotic fluid) during pregnancy
• When a baby is born, the intestines and occasionally other organs like the liver stay inside the umbilical cord but outside the abdomen due to an umbilical hernia or another abnormality of the abdominal wall (Omphalocele)
• Abnormally enlarged organs - Hepatomegaly (abnormally enlarged liver), Nephromegaly (abnormally enlarged kidneys), or both
• A large tongue size (Macroglossia) 
• Weight gain and increased height during childhood or at birth (>2 SDS (standard deviation scores) above the mean for birth weight)
• Growth that is asymmetrical, such as one limb or leg growing larger than the other (hemihypertrophy)
• Neonatal and/or temporary Hypoglycemia (low blood sugar) and Hyperinsulinemia (elevated levels of insulin) 
• Kidney Wilms' tumour and other embryonal tumours (adrenocortical carcinoma, hepatoblastoma, isolated Wilms’ tumour, neuroblastoma, or pheochromocytoma)
• Cutaneous simplex nevi (also known as “stork bites” or “angel kisses”)
• Wrinkles or pits in the ears

Causes and genetics

Given the unique clinical presentation of each patient, BWS has recently been reclassified as the Beckwith-Wiedemann Spectrum. This spectrum encompasses a range of manifestations, with chromosome alterations that appear random or erratic found in approximately 80% of individuals with BWS. While about 5-10% of cases are inherited, roughly 14% have an unknown cause. The condition affects at least 1 in approximately 10,000 live births.¹

BWS is primarily caused by anomalies in chromosome 11p15, which disrupt the normal expression of genes critical for growth in this region.⁴ Genetic changes and mutations affecting key genes are generally responsible for the syndrome. One significant gene, CDKN1C, is essential for regulating cell division and development.⁴ Mutations in CDKN1C can lead to cell overgrowth, contributing to the distinctive features of BWS. Additionally, variations in the IGF2 gene, which is vital for fetal growth, can further influence the condition's manifestations.⁵

Diagnosis

Clinical evaluation and physical examination

BWS is a congenital overgrowth disorder affecting approximately 1 in 10,000 babies. Diagnosis is typically made through a combination of evaluating clinical features and molecular testing. Today, molecular testing is usually conducted via a simple blood test arranged by a paediatrician or clinical geneticist. This testing yields positive results in about 80% of children with BWS. If molecular testing is negative, a clinical geneticist will advise on whether a diagnosis can still be made based solely on clinical evidence.^4,6

Therefore, physical examinations are commonly used to diagnose BWS. Additionally, the following assessments can help identify the syndrome:

• A thorough review of the child's medical history and family background
• Genetic testing, either before or after birth
• Blood tests for low blood sugar levels
• Abdominal ultrasound

Prenatal testing

Healthcare professionals often cannot diagnose BWS before birth, although prenatal ultrasounds may sometimes reveal indicators of potential issues related to the disease. If ultrasounds suggest the possibility of BWS, healthcare providers may use amniocentesis or chorionic villus sampling to detect the condition before birth.⁸ These procedures involve obtaining samples from the amniotic fluid or the placenta, respectively, to analyse the genetic material for any abnormalities associated with BWS.  This prenatal genetic testing, however, is a personal decision, and it is important to discuss the options with your healthcare provider or a genetic counsellor. They can explain the procedures in detail, outline the potential risks and benefits, and help you understand how the results might impact your pregnancy and the management of your child’s health.

Ultimately, whether or not to proceed with prenatal genetic testing for BWS is a choice that you and your family need to make based on your circumstances, preferences, and the information provided by your healthcare team.

Associated complications and cancer

Most of the health issues associated with BWS are predictable and manageable, particularly concerning tumour development. Typically, tumours related to BWS tend to appear within the first 8–10 years of life.^3,4 The most common tumours in BWS are hepatoblastoma and Wilms' tumour. Other types of embryonal tumours that may occur include rhabdomyosarcoma, adrenocortical carcinoma, and neuroblastoma.^3,4

The overall risk of developing tumours in children with BWS has been estimated to range between 4% and 21%, with an average risk of about 7.5%.⁹ Clinical signs that indicate an increased risk of tumour development include hemihyperplasia (asymmetric overgrowth of one side of the body), nephromegaly (enlarged kidneys), and nephrogenic rests (clusters of kidney cells that may become cancerous).^3,4

Several factors can contribute to the risk of BWS-related tumours. Premature birth, discordant monozygotic twinning (where twins develop from a single fertilized egg but differ in growth patterns, with a higher prevalence in females), and neonatal hypoglycemia (low blood sugar in newborns) are associated with an increased risk. Notably, while neonatal hypoglycemia itself is not considered a congenital abnormality, poorly managed hypoglycemia in infancy is thought to be a significant factor contributing to lower IQ levels reported in some children with BWS.⁹

Management and treatment

A multidisciplinary approach is essential for effective BWS treatment, given its range of symptoms and potential complications. Each patient’s specific symptoms are addressed with targeted treatments, often requiring the coordinated efforts of a diverse team of medical specialists.

A comprehensive treatment plan for a child with BWS may involve collaboration among various professionals, including:^1,3,4,9

• Geneticists: To manage genetic aspects and provide insights into the genetic mutations associated with BWS
• Paediatricians: To oversee general health and development, coordinating care and monitoring overall well-being
• Plastic Surgeons: To address physical anomalies and perform necessary surgical interventions
• Endocrinologists: To manage hormonal imbalances and growth issues related to BWS
• Nephrologists: To monitor and treat any kidney-related issues or complications
• Orthodontists: To address dental and orthodontic needs, which may be affected by the syndrome
• Pulmonologists: To manage any respiratory issues that might arise
• Speech Pathologists: To support and address any speech or language delays
• Pediatric Oncologists: To monitor and treat any tumours or malignancies associated with BWS

The collaboration of these specialists ensures a well-rounded and thorough approach to treating BWS, tailored to the individual needs of each patient. This coordinated effort helps in managing the syndrome’s complex symptoms and improving the overall quality of life for affected children.¹

Surgical and medical interventions for BWS

Management of Beckwith-Wiedemann Syndrome (BWS) often involves a combination of surgical and medical interventions tailored to address the specific needs of the patient:^1,2

• Surgical Repair: Procedures may be performed on the abdominal wall to correct conditions such as umbilical hernias or omphalocele, which are common in BWS.
• Medical Treatment for Hypoglycemia: Hypoglycemia, or low blood sugar, can be managed effectively with medication to maintain stable blood sugar levels and prevent associated complications.
• Treatment for Macroglossia: Surgery to reduce the size of the tongue may be necessary to treat macroglossia, a condition characterised by an abnormally large tongue that can cause difficulties with eating and speaking.
• Orthotic and Length Adjustment: To address any discrepancies in leg length, orthotics may be used to balance the appearance and function of the legs. Additionally, various techniques can be employed to manage and correct inconsistencies in leg length.

These interventions are designed to address the specific symptoms and challenges associated with BWS, improving the quality of life and overall well-being of affected individuals.

Prognosis

The prognosis for BWS varies widely depending on the severity of the condition. In more severe cases, complications such as hypoglycemia-related issues, premature birth, cardiomyopathy, macroglossia, and tumours can lead to infant, neonatal, or childhood mortality. Conversely, children with milder forms of BWS often experience only minor issues that do not significantly impact their quality of life.^1,3,4,9

Recent research indicates that individuals with BWS are at an increased risk of developing tumours during childhood. Routine screening is crucial for the early detection and management of these tumours. Additionally, BWS-related complications such as omphalocele, hyperinsulinism, and macroglossia may require ongoing medical care. Despite these potential challenges, many individuals with BWS can expect a typical life expectancy. However, data on outcomes for adults with BWS remain limited and warrant further study.⁷

Summary

Beckwith-Wiedemann Syndrome (BWS) is a rare genetic condition characterised by overgrowth and an increased risk of malignancy, affecting approximately 1 in 10,000 births. This syndrome presents a range of physical features and symptoms, including asymmetrical limb growth, a large tongue (macroglossia), and a higher incidence of childhood cancers. In about 80% of cases, BWS is associated with random chromosome alterations, particularly affecting growth-regulating genes on chromosome 11. Diagnosis of BWS involves clinical evaluation and genetic testing, with some cases identified prenatally through invasive diagnostic procedures. Due to the heightened risk of childhood cancers associated with BWS, regular screenings and early management are crucial. Treatment for BWS requires a comprehensive approach, focusing on addressing specific symptoms through both surgical and non-surgical methods. Surgical interventions may be necessary for conditions such as limb length discrepancies, macroglossia, and umbilical hernias. Managing BWS effectively involves routine monitoring and controlling tumour risk, with early intervention and surgical excision as needed. The prognosis for individuals with BWS can vary widely. Severe cases may result in early mortality, while milder forms may have minimal impact on quality of life. Early detection, diligent monitoring, and a well-coordinated treatment plan can significantly improve the well-being of those affected by BWS.