Beckwith Wiedemann Syndrome: Symptoms, Types, Causes and Treatment

Beckwith-Wiedemann Syndrome (BWS) is a rare genetic disorder that stands at the crossroads of overgrowth syndromes and cancer predisposition. Though uncommon, BWS is the most frequent congenital overgrowth syndrome, recognized for its complex blend of physical features, genetic underpinnings, and medical challenges. This article aims to unravel the key aspects of BWS, from its diverse symptoms and molecular types to the causes driving the disease and the modern approaches to treatment and management.

Symptoms of Beckwith Wiedemann Syndrome

Beckwith-Wiedemann Syndrome is characterized by a spectrum of clinical features that can vary widely from one individual to another. While some children present with the classic triad—macroglossia (large tongue), overgrowth, and abdominal wall defects—others may show only a subset of signs. Early recognition is crucial for management, especially given the risk of neonatal complications and childhood cancers.

Symptom	Description	Frequency/Significance	Source(s)
Macroglossia	Enlarged tongue, often protruding	Most common feature	1 2 3 10 12
Overgrowth	Prenatal/postnatal macrosomia, tall stature	Classic feature	1 3 7 10 12
Abdominal Defects	Omphalocele, umbilical hernia	Core diagnostic sign	1 2 3 10 12
Hypoglycemia	Low blood sugar in the neonatal period	Potentially life-threatening	1 2 12
Hemihyperplasia	Asymmetric body/limb overgrowth	Variable	1 10 12
Ear Anomalies	Creases, pits, or structural abnormalities	Variable	1 3 10
Nevus Flammeus	Facial birthmark (port-wine stain)	Sometimes present	1 10
Renal Anomalies	Kidney/urinary tract malformations	Increased tumor risk	1 10 12
Embryonal Tumors	Wilms tumor, hepatoblastoma, others	Increased childhood risk	6 10 12 14
Neonatal Mortality	Complications from symptoms (e.g., hypoglycemia, airway obstruction)	Risk in severe cases	2 12

Table 1: Key Symptoms

Classic and Variable Features

Classic Symptoms
The hallmark features—macroglossia, overgrowth, and abdominal wall defects—are central to BWS diagnosis. Macroglossia is observed in the majority of patients, sometimes causing feeding or breathing difficulties that may require intervention 1 2 3 12 16 17. Overgrowth can be prenatal (detected on ultrasound) or postnatal, often resulting in a large birth weight and rapid growth during infancy 1 3 7 10 12. Abdominal wall defects like omphalocele or umbilical hernia can be present at birth and may need surgical repair 1 2 3 10 12.

Variable and Additional Symptoms
BWS can also present with:

• Hemihyperplasia: Uneven growth of one side of the body or limb 1 10 12.
• Ear anomalies: Notches, creases, or malformed ears 1 3 10.
• Nevus flammeus: A reddish birthmark, usually on the forehead or eyelids 1 10.
• Renal and urinary tract anomalies: These increase the risk for Wilms tumor, a childhood kidney cancer 1 10 12.

Complications
Hypoglycemia is common in the neonatal period and can be severe, requiring immediate attention to prevent brain damage 1 2 12. There is also an increased risk of developing embryonal tumors, especially in early childhood, making regular screening essential 6 10 12 14. Rarely, severe cases may experience neonatal mortality due to complications of prematurity, severe macroglossia (airway obstruction), or cardiac issues 2 12.

Neuropsychological and Social Impact
Some studies have observed heightened rates of anxiety and socialization difficulties in children with BWS, along with increased caregiver burden 4. Psychological support for families is important for holistic care.

Types of Beckwith Wiedemann Syndrome

BWS is not a single entity but encompasses a spectrum of clinical and molecular subtypes. Understanding these types is vital for appropriate diagnosis, risk assessment, and tailored management.

Type/Subgroup	Key Molecular Feature	Distinct Clinical Features	Source(s)
IC1-GoM	Gain of methylation at Imprinting Center 1	Extreme macrosomia, Wilms tumor risk	6 7 9 10 18
IC2-LoM	Loss of methylation at Imprinting Center 2	Exomphalos, ear anomalies, low tumor risk	6 7 9 10 18
UPD (11p15 UPD)	Paternal uniparental disomy at 11p15	Hemihyperplasia, risk of Wilms tumor and hepatoblastoma	6 7 9 10 18
CDKN1C Mutation	Mutation in CDKN1C gene	Exomphalos, neuroblastoma risk, prematurity	6 7 9 10 18
MLID	Multi-locus imprinting disturbance	Heterogeneous; often female, variable presentation	9
Classical/Clinical	No molecular diagnosis, based on phenotype	Macroglossia, overgrowth, abdominal wall defects	10 14 15

Table 2: Key Types of BWS

Molecular Subtypes and Their Implications

IC1 Gain of Methylation (IC1-GoM)

• Characterized by excessive methylation at Imprinting Center 1 on chromosome 11p15.
• Presents with pronounced overgrowth (macrosomia), high risk for Wilms tumor, and renal anomalies 6 7 10.
• Neonatal macrosomia is nearly universal; body proportions may be notably abnormal 7.

IC2 Loss of Methylation (IC2-LoM)

• Involves loss of methylation at Imprinting Center 2.
• More likely to have exomphalos and ear anomalies, but lower risk of Wilms tumor 6 7 10.
• Prematurity is more frequent; overgrowth is less extreme and more proportionate 7 10.

Paternal Uniparental Disomy (UPD)

• Both copies of the 11p15 region are inherited from the father.
• Associated with hemihyperplasia, risk for Wilms tumor and hepatoblastoma, and renal anomalies 6 7 10.
• Growth patterns are intermediate between IC1-GoM and IC2-LoM 7.

CDKN1C Mutations

• Mutations in the maternal CDKN1C gene, a tumor suppressor regulating cell growth.
• More likely to have exomphalos and neuroblastoma, with higher rates of prematurity 6 7 10.

Multi-Locus Imprinting Disturbance (MLID)

• Methylation defects extend beyond BWS-specific loci.
• Presentation is variable; more common in females and in cases related to assisted reproduction 9.

Clinical Spectrum and Overlap

Complete and Incomplete Forms

• Some patients present with the full array of classic symptoms (complete form), while others show only a subset (incomplete form) 5 8 10.
• The clinical variability often parallels underlying molecular differences, but overlap is common 8 10.

Clinical Diagnosis Without Molecular Confirmation

• Not all patients fit neatly into molecular subgroups, and a clinical diagnosis is sometimes made based on phenotype alone 14 15.

Causes of Beckwith Wiedemann Syndrome

BWS arises from complex genetic and epigenetic changes affecting growth-regulating genes on chromosome 11p15. These alterations disrupt the tightly controlled balance of gene expression established through genomic imprinting.

Cause	Mechanism/Genetic Event	Clinical Impact/Notes	Source(s)
Imprinting Defects	Abnormal methylation at 11p15 regions	Dysregulation of growth genes	1 11 12 13
Uniparental Disomy (UPD)	Two paternal copies of 11p15	Overexpression of paternally active genes	1 6 7 10
CDKN1C Mutations	Loss-of-function in growth suppressor	Overgrowth, increased tumor risk	1 10 13
Assisted Reproduction	Higher incidence after ART	Suggests epigenetic vulnerability	1 3 9
Multi-Locus Imprinting	Widespread methylation defects	Broader/atypical features	9
Sporadic Mutation/Epimutation	Not inherited, occur de novo	Most common; low familial recurrence	1 3 12 13

Table 3: Causes of BWS

Genetic and Epigenetic Mechanisms

Imprinting Disturbance on Chromosome 11p15

• BWS is a model imprinting disorder involving two domains on chromosome 11p15: Domain 1 (IGF2/H19) and Domain 2 (KCNQ1, KCNQ1OT1, CDKN1C) 1 11 12 13.
• Imprinted genes are expressed in a parent-of-origin specific manner, regulated by methylation marks established during gamete formation 1 11.
• Disruption—by mutation or abnormal methylation—leads to inappropriate gene expression, driving overgrowth and cancer risk.

Uniparental Disomy (UPD)

• Occurs when both copies of the critical region are inherited from the father (uniparental isodisomy), resulting in double dosage of paternally expressed growth promoters like IGF2 1 6 7 10.

CDKN1C Mutations

• CDKN1C is a maternally expressed tumor suppressor gene. Mutations or silencing lead to unchecked cell growth 1 10.

Multi-Locus Imprinting Disturbance (MLID)

• In some cases, methylation defects are not limited to 11p15 but affect multiple imprinted loci, leading to broader or atypical presentations 9.
• MLID is more common in females and is associated with assisted reproductive technologies 9.

Environmental and Inherited Factors

Sporadic vs. Familial Cases

• The majority of BWS cases are sporadic, arising from de novo mutations or epimutations, with a low risk of recurrence in siblings 1 3 12 13.
• Rare familial cases are usually due to heritable CDKN1C mutations 13.

Assisted Reproductive Technology (ART)

• A higher incidence of BWS has been observed in children conceived via ART, suggesting that external factors during early embryonic development may disrupt imprint establishment 1 3 9.

Treatment of Beckwith Wiedemann Syndrome

Management of BWS is multidisciplinary and individualized, reflecting the syndrome’s complexity and variability. The main goals are to address immediate health risks, monitor and prevent complications, and support optimal long-term outcomes.

Treatment Approach	Purpose/Target	Notes/Indications	Source(s)
Neonatal Management	Address hypoglycemia, airway issues	Immediate postnatal intervention	2 12 14
Surgery (Macroglossia)	Reduce tongue size, prevent obstruction	Indicated for severe macroglossia	16 17
Surgery (Abdominal wall)	Repair omphalocele/hernia	Early surgical correction	1 12 14
Tumor Surveillance	Early detection of Wilms tumor, etc.	Protocols tailored by molecular subtype	6 10 14 15 18
Genetic Counseling	Inform families of recurrence risk	Especially in familial/molecular cases	13 14 15
Psychological Support	Address anxiety, socialization issues	For patients and families	4 14 15
Long-term Follow-up	Monitor growth, development, cancer risk	Multidisciplinary care	14 15 18

Table 4: Treatment Approaches in BWS

Acute Management

Neonatal Hypoglycemia and Airway Support

• Immediate intervention is crucial for hypoglycemia—frequent monitoring and intravenous glucose may be required 2 12 14.
• Macroglossia can cause feeding and breathing difficulties; airway management may include positioning, feeding modifications, or early surgery in severe cases 1 12 14 16 17.

Surgical Treatments

Macroglossia Surgery

• Surgical tongue reduction is indicated for severe cases to prevent airway obstruction, dental deformities, and speech difficulties 16 17.
• Techniques vary; anterior wedge resection is common and effective. Most patients have satisfactory outcomes, with few long-term complications 16 17.

Abdominal Wall Repair

• Omphalocele or umbilical hernias are repaired surgically, often in the neonatal period 1 12 14.

Tumor Surveillance and Screening

Cancer Risk and Screening Protocols

• Regular abdominal ultrasounds and blood tests (e.g., alpha-fetoprotein) are recommended during early childhood to detect tumors such as Wilms tumor and hepatoblastoma 6 10 14 15 18.
• Surveillance intensity is tailored to the patient’s molecular subtype, with higher-risk genotypes (IC1-GoM, UPD) receiving more frequent screening 6 10 14 15 18.

Multidisciplinary and Supportive Care

Long-term Monitoring

• Ongoing assessment of growth, development, renal function, and psychological well-being is essential 14 15 18.
• Interdisciplinary clinics are ideal for coordinated care 16.

Genetic Counseling

• Families benefit from counseling regarding recurrence risks, especially in cases with a defined genetic mutation 13 14 15.

Psychological and Social Support

• Children with BWS may experience anxiety and socialization challenges; families may face significant stress 4 14 15.
• Access to mental health resources and support groups is important for quality of life.

Conclusion

Beckwith-Wiedemann Syndrome is a complex and multifaceted disorder that requires personalized, multidisciplinary care. Early recognition and diagnosis facilitate optimal management, reduce neonatal risks, and allow for effective tumor surveillance.

Key takeaways:

• Symptoms: BWS features a variable combination of overgrowth, macroglossia, abdominal wall defects, hypoglycemia, hemihyperplasia, and increased tumor risk 1 2 3 10 12.
• Types: Molecular subtypes (IC1-GoM, IC2-LoM, UPD, CDKN1C mutations, MLID) correlate with different clinical features and cancer risks 6 7 9 10 14 18.
• Causes: BWS is caused by genetic and epigenetic disturbances of imprinted genes on chromosome 11p15, with contributions from both inherited and sporadic events. ART is a recognized risk factor 1 3 9 11 12 13.
• Treatment: Management involves acute neonatal care, surgical correction of abnormalities, tumor surveillance tailored to molecular risk, genetic counseling, and psychological support 6 10 14 15 16 17 18.
• Prognosis: With early intervention and personalized follow-up, many children with BWS lead healthy lives, though ongoing monitoring remains crucial.

By understanding the nuanced landscape of BWS, healthcare providers and families can work together to navigate challenges and foster the best possible outcomes.