Beckwith-Wiedemann Syndrome

Description

Beckwith-Wiedemann Syndrome (BWS) is a congenital overgrowth syndrome that manifests with physical overgrowth, organomegaly, and an increased risk of embryonal tumours. While it’s part of the spectrum of imprinting disorders, it’s predominantly associated with anomalies in the chromosomal region 11p15. BWS is not typically inherited; instead, most cases are due to sporadic genetic and epigenetic changes that disrupt the normal balance of growth regulation during early embryonic development.

Pathogenesis

The pathogenesis of BWS is primarily attributed to alterations within the 11p15.5 chromosomal region that disrupts normal imprinting, which involves silencing one copy of a gene based on its parent of origin. Two key areas within this region, namely imprinting control regions 1 and 2 (IC1 and IC2), are particularly implicated. The IC1 region controls the expression of IGF2, a growth-promoting gene, and H19, a growth-limiting gene. The IC2 region regulates CDKN1C, a gene that restrains cell proliferation. The syndrome can arise from various genetic and epigenetic changes, including uniparental disomy, IC1 or IC2 loss of methylation, CDKN1C mutations, and others.

Subtypes

There are no well-defined subtypes of BWS; however, the disease presentation can vary widely. This variance is often correlated with the specific genetic or epigenetic alterations, for instance, patients with IC2 loss of methylation often present with an exomphalos.

Epidemiology, Risk Factors & Associations

• BWS affects approximately 1 in 13,700 live births, suggesting a considerable sporadic mutation rate.
• The syndrome does not favour any particular sex or racial group.
• BWS patients are predisposed to develop embryonal tumours, notably Wilms’ tumour and hepatoblastoma, with a risk estimated around 7.5%.
• Associated with perilobar nephroblastomatosis.

Clinical Features

• Macrosomia refers to an excessive birth weight that can persist as general overgrowth in childhood.
• Macroglossia, or an enlarged tongue, can lead to feeding and speech difficulties, and possibly obstructive sleep apnoea.
• Abdominal wall defects, often presenting as exomphalos, can also occur.
• Ear creases or pits are minor anomalies seen often in BWS.
• Neonatal hypoglycaemia, due to hyperinsulinism, is frequently observed.
• Organomegaly, particularly of the liver, kidneys, and pancreas, is common.
• Hemihypertrophy or asymmetrical overgrowth of the body can occur.
• BWS patients have an increased risk of embryonal tumours, most commonly Wilms’ tumour and hepatoblastoma (second most common).

Complications

• Hypoglycaemia can lead to seizures or brain damage if severe and untreated.
• Feeding difficulties due to macroglossia may lead to poor nutrition.
• Speech difficulties due to macroglossia can hinder communication skills.
• Obstructive sleep apnoea due to macroglossia can cause interrupted sleep and contribute to developmental issues.
• Learning difficulties may be experienced despite normal IQ.
• Increased tumour risk, most significantly Wilms’ tumour, requires regular surveillance.
• An increase in size of nephroblastomatosis may indicate transformation to Wilms’ tumour

Pathological Features

Histopathology

• Macroscopic: The findings are dependent on the affected organs, most notable being large body size (macrosomia), enlarged organs (organomegaly), and tumour growth.
• Microscopic: The changes are variable depending on the specific organs involved. In cases of tumour development, histology will be characteristic of the specific tumour type.

Serology

• Hypoglycaemia may be detected in neonatal period.
• Tumour markers could be elevated if there’s a development of tumour.

Biochemistry

• There are no specific biochemical changes associated with BWS, unless complications such as hypoglycaemia or tumour development occur.

Radiological Features

General Features

• Generally reflect physical overgrowth and organomegaly.
• Wilms’ tumour often presents as a large, well-defined abdominal mass, which can be heterogeneous due to areas of haemorrhage, necrosis, and cystic changes.
• Hepatoblastoma may appear as a hyperechoic or mixed echogenicity mass in the liver on ultrasound, and as a heterogeneously enhancing lesion on CT/MRI. Calcifications may be present.
• Imaging also helps in the assessment of abdominal wall defects such as exomphalos.
• Nephroblastomatosis appears as nodular rind of homogeneous low signal subcapsular masses

US

• Foetal ultrasound: Can detect features such as macrosomia, omphalocele, macroglossia, and organomegaly. Placental enlargement is also commonly seen.
• Postnatal ultrasound: Important for ongoing surveillance of tumour development, particularly Wilms’ tumour and hepatoblastoma.

Grading and Staging

Grading and staging is not relevant to the syndrome itself; however, any tumours that develop in the context of BWS would be graded and staged according to their specific type and guidelines, such as TNM staging for hepatoblastoma and the staging system for Wilms’ tumour.

Diagnosis

Diagnosis of BWS is typically made on the presence of major (macrosomia, macroglossia, and abdominal wall defects) and minor (ear pits, neonatal hypoglycaemia, organomegaly, hemihypertrophy) clinical features. Molecular testing can confirm the diagnosis with identification of abnormalities in the 11p15.5 chromosomal region.

Differential Diagnosis

• Simpson-Golabi-Behmel syndrome: A genetically distinct X-linked overgrowth syndrome with similar but often more severe features.
• Perlman syndrome: Presents with macrosomia, renal anomalies and an increased risk of Wilms’ tumour.
• Isolated hemihypertrophy: Characterised by asymmetrical body growth but lacks other features of BWS.
• Maternal diabetes: Can also lead to macrosomia but doesn’t present with other features of BWS.

Management

Management of BWS is multidisciplinary, involving paediatricians, geneticists, surgeons, speech therapists, and other specialists as needed. Management focuses on addressing specific issues like hypoglycaemia, abdominal wall defects, macroglossia, and hemihypertrophy. Regular tumour surveillance, primarily for Wilms’ tumour and hepatoblastoma, is crucial and typically involves abdominal ultrasound every three months until the age of eight.