Beckwith-Wiedemann Syndrome

Definition of the Disease. Causes of the Condition

Beckwith-Wiedemann Syndrome (BWS) is a genetic disorder characterized by a triad of features: excessive growth and weight, large tongue, and omphalocele (protrusion of abdominal organs at the umbilical ring). The disease is also referred to as gigantism syndrome with umbilical hernia.
Additional features include hemihyperplasia (one side of the body growing larger than the other), separation of the abdominal muscles, umbilical hernia, embryonal tumors, enlargement of the adrenal cortex and internal organ sizes, kidney anomalies, low glucose levels in the first month of life, earlobe notches, and characteristic facial features. The latter characteristic is more recognizable in infancy and becomes less obvious in older age.

Beckwith-Wiedemann syndrome


Beckwith-Wiedemann Syndrome (BWS) is identified in 1 in 13,700 children, with boys and girls equally affected. However, the condition may actually occur more frequently, as those with milder symptoms may not be diagnosed. The prevalence of the syndrome is not dependent on geographic, ethnic, or social factors.
Hemihyperplasia is detected in 1 in 86,000 patients, more commonly in girls.
Causes of Beckwith-Wiedemann Syndrome
About 85% of BWS cases occur sporadically, while only 15% are inherited from parents.
The main causes and risk factors for this condition include:

  1. Genetic mutations. Most BWS cases result from genetic mutations. One of the key genes responsible for normal growth and development regulation is CDKN1C. Mutations in this gene are considered the most common cause of Beckwith-Wiedemann Syndrome. Although 85% of cases arise from new mutations and the disease has not previously occurred in the family, sometimes, in 15% of cases, damaged genes are passed down from one of the parents. A child inheriting the altered gene may not have any characteristic signs of this condition; they are more often present if the gene is received from the mother. More detailed genetic reasons are presented in the table below.
  2. Epigenetic changes. These changes are not related to mutations but to how genes are regulated in the body. Typically, healthy individuals have regulatory mechanisms in the genome that allow for proper control of gene expression – the process by which genetic information from DNA is converted into RNA or protein. If these mechanisms do not work properly, changes in DNA methylation or chromatin packaging may occur, which can decrease or increase gene expression, including those responsible for the development of BWS. Some epigenetic changes may occur during pregnancy due to abnormal placental development or other factors such as smoking, nutrient deficiency, or stress.

Genetic and Epigenetic Causes of BWS

Molecular GroupsFrequencyInheritance
Loss of methylation of the IC2 gene (KCNQ1OT1) on the maternal chromosome50%First occurrence in the family
Paternal uniparental disomy20%First occurrence in the family
Mutation of the CDKN1C gene5%40% from a parent; Mostly from the mother
Hypermethylation of IC1 (H19) on the maternal chromosome5%First occurrence in the family; If with deletion, inherited from the mother
Cytogenetically visible duplication of chromosome 11p15<1%Inherited from the father
Chromosome translocation or inversion<1%Inherited from the mother
  1. Assisted Reproductive Technologies: The use of in vitro fertilization (IVF) increases the risk of developing BWS by 4 times. However, not all studies confirm this result, and it does not necessarily mean that IVF always leads to BWS. The mechanism by which IVF more commonly leads to BWS is not fully understood.
  2. Maternal age and repeated pregnancies can also increase the risk of developing BWS.

Symptoms of Beckwith-Wiedemann Syndrome

The clinical presentation of BWS is heterogeneous and may vary among different patients. Some symptoms of the disease may manifest with age, while some signs are present immediately after birth.

Key symptoms of Beckwith-Wiedemann Syndrome include:

  • Macroglossia: enlarged tongue, often noticeable immediately after birth. The tongue may protrude beyond the oral cavity and affect feeding. The size of the tongue can be so large that it may obstruct the airways, leading to breathing difficulties, as well as speech delay in older children.
  • Omphalocele: manifested by a defect in the umbilical ring through which abdominal organs protrude, this condition can be detected on prenatal ultrasound screening.
  • Hemihypertrophy: asymmetric growth of one side of the body compared to the other.
  • Neonatal hypoglycemia: low blood glucose levels in the first month of life, occurring in approximately half of children with BWS. It may present with tremors, drowsiness, rapid heartbeat, feeding difficulties, seizures with loss of consciousness, and in severe cases, coma.
  • Embryonal tumors: patients with BWS have an increased risk of developing malignant neoplasms such as Wilms’ tumor (embryonal kidney cancer) and hepatoblastoma (liver tumor).
  • Insufficient immune defenses: some patients may have a deficiency in immunoglobulins IgA, IgG, or IgM classes, increasing the risk of infections.
  • Various kidney and urinary tract defects: in some cases, anomalies in kidney and urinary tract function are detected, leading to urinary dysfunction.
  • Splanchnomegaly: enlargement of abdominal internal organs (liver, pancreas, spleen, etc.).
  • Anterior earlobe creases and/or posterior helical pits (on one ear or both).
Anterior folds of the earlobe

Pathogenesis of Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann Syndrome (BWS) develops due to various genetic and epigenetic causes. These changes disrupt the functioning of genes on the p15 region of chromosome 11, responsible for the growth and development of the embryo and placenta. Within this gene cluster, there are two regions: telomeric and centromeric. The telomeric region includes the H19 and IGF2 genes, while the centromeric region includes KCNQ1, KCNQ1OT1, and CDKN1C.

For instance, CDKN1C encodes a protein that restricts cell division and growth, while IGF2 is an insulin-like growth factor that stimulates growth. Disruptions associated with these genes can lead to various forms of Beckwith-Wiedemann Syndrome. For example, disruption of CDKN1C expression may result in overgrowth of many tissues, which is a common manifestation of BWS. Approximately half of patients with this condition are found to have adrenocortical tumors, as well as tumors of muscles and kidneys.

Classification and Stages of Beckwith-Wiedemann Syndrome

In the International Classification of Diseases (ICD-10), Beckwith-Wiedemann Syndrome belongs to subgroup Q87.3 – Syndromes with congenital anomalies manifesting as excessive growth (gigantism) in early development stages. Syndromes such as Sotos and Weaver syndromes also belong to Q87.3.

Complications of Beckwith-Wiedemann Syndrome

The most dangerous complications of BWS are cancerous tumors, such as Wilms’ tumor, hepatoblastoma, and mesoblastic nephroma. With early diagnosis and timely treatment, these neoplasms do not lead to the death of the child. However, patients still have a high risk of death due to multiple congenital anomalies and multiorgan disorders, i.e., changes in the functioning of several organs simultaneously. Up to 20% of children with BWS die from these complications.

Diagnosis of Beckwith-Wiedemann Syndrome

BWS can be suspected during pregnancy using ultrasound screening. In such cases, childbirth should take place in a specialized center with a pediatric surgery department and neonatal intensive care unit.

History Taking and Examination

Various methods are used for diagnosing Beckwith-Wiedemann Syndrome. Firstly, the physician examines the child, collects complaints, and gathers the medical history (history of illness) from the parents. When collecting family history, the doctor will inquire about enlarged tongue at birth and tumors among relatives.

The child usually exhibits excessive growth and weight, large tongue, body asymmetry, and defects of the anterior abdominal wall such as omphalocele or umbilical hernia.

Physical examination can also assist in diagnosing BWS. For this purpose, a table of diagnostic criteria is used, which includes major and minor signs. To make a diagnosis, the presence of three major signs or two major and one minor sign is required.

Major signs include:

  • Defect of the anterior abdominal wall: omphalocele or umbilical hernia;
  • Macroglossia (enlarged tongue);
  • Macrosomia (excessive growth and weight, height and weight > 97th percentile – a special macrosomia calculator available online can be used for calculation);
  • Anterior earlobe creases and/or posterior helical pits (on one ear or both);
  • Enlargement of the liver, kidneys, spleen, pancreas, and adrenal glands;
  • Embryonal tumors in childhood;
  • Hemihyperplasia (one side of the body growing more than the other);
  • Enlargement of the adrenal cortex, usually diffuse and bilateral;
  • Kidney anomalies, including medullary dysplasia with subsequent development of medullary sponge kidney;
  • Cases of BWS in the family;
  • Cleft palate.

Minor signs include:

  • During pregnancy: polyhydramnios, large placenta and/or thick umbilical cord;
  • Premature birth;
  • Low blood glucose level in the first month of life;
  • Flame nevus;
  • Cardiomegaly (enlargement of the heart), structural heart anomalies, or cardiomyopathy (heart muscle involvement);
  • Accelerated bone age;
  • Separation of the abdominal muscles;
  • Characteristic facial features.
Characteristic face of SWS

For example, if a child has macroglossia and umbilical hernia, i.e., only two major signs, and no minor signs, BWS is not diagnosed, and the doctor continues the examination to detect other diseases.

Laboratory and Instrumental Diagnosis

Laboratory and instrumental diagnostics are conducted after physical examination. It is recommended to undergo blood tests for glucose, insulin, AFP (alpha-fetoprotein), calcium, and creatinine levels.

Instrumental diagnostic methods for BWS include echocardiography (EchoCG), electrocardiography (ECG), X-rays, CT scans, MRI scans, and ultrasound (US).

EchoCG and ECG can be used to evaluate heart function since patients often have cardiomegaly and other structural heart anomalies. These methods can also help identify cardiomyopathy.

X-rays, CT scans, MRI scans, and ultrasound can provide additional information about changes in organs and tissues. Signs of BWS may include splenomegaly (enlargement of internal organs), which may indicate the presence of tumors.

Genetic Testing

To confirm the diagnosis definitively, genetic testing is necessary. BWS is caused by changes in various genes, so laboratory diagnostics include analysis of several genetic mutations (KCNQ1OT1, H19, and CDKN1C genes).

Additional Diagnostic Methods

For children over one year old, cognitive abilities are assessed. This is especially relevant for infants with developmental delay or other nervous system disorders – low blood glucose levels in the first months after birth can lead to brain damage.

Differential diagnosis

BWS must be distinguished from syndromes that also present with macrosomia.

SyndromeSimilarity to BWSDifferences from BWS
Simpson-Golabi-Behmel Syndrome– Increased growth and weight of the child.– Coarse facial features: mongoloid eye slant (outer corners of the eyes are lower than inner), midline groove on the lower lip; cleft lip; structural heart anomalies and conduction disturbances; skeletal anomalies, including polydactyly (extra fingers on hands or feet); developmental delay.
Perlman Syndrome– Macrosomia.– Characteristic facial features (small upper or lower jaw, low-set ears, depressed nasal bridge, inverted V-shaped upper lip border); high mortality in the first month of life; significant intellectual impairments.
Costello Syndrome– Symptoms manifest only in the neonatal period (up to 28 days of life).– Cardiac dysfunctions; developmental delays; coarsening of facial features.
Sotos Syndrome– Macrosomia.– Characteristic facial features (long and narrow head shape, frontal bossing, mongoloid eye slant, pointed chin); sparse hair in the frontal-temporal region; intellectual disability; macrocephaly (enlargement of the head and brain).
Mosaic Paternal Uniparental Disomy Syndrome– Large weight for gestational age; large placenta; macrosomia; low blood glucose levels due to insulin excess; umbilical hernia; liver enlargement; hemangioma; increased risk of kidney, liver, and adrenal tumors.– Severe developmental delay; features typical of imprinting disorders.
Treatment for Beckwith-Wiedemann Syndrome (BWS)

Treatment for Beckwith-Wiedemann Syndrome (BWS) primarily focuses on managing symptoms as it is a genetic condition without a cure. The approach to treatment should be tailored to each individual patient’s needs, often requiring a multidisciplinary approach involving endocrinologists and surgeons.

Hypoglycemia, occurring in 30-60% of BWS patients due to insulin excess, may necessitate medical intervention such as glucose infusion, diazoxide, or somatostatin administration until hypoglycemic episodes cease. In severe cases, subtotal pancreatectomy, removing part of the pancreas, may be required.

Macroglossia, present in 90% of BWS patients, can usually be managed as facial bones grow, allowing better tongue control over time. Speech defects resulting from mild to moderate macroglossia can be corrected with speech therapy. Surgical intervention, such as partial tongue resection, may be necessary for severe cases causing breathing, feeding, speech, or articulation difficulties.

Abdominal wall defects may also be observed and require consultation with a surgeon for appropriate management, possibly involving surgical repair.

Excessive growth and asymmetric development of body parts are common symptoms in approximately half of BWS patients. Treatment may involve footwear fitting or surgical correction of leg length discrepancies.

Prognosis and Prevention:
  • Most BWS patients lead ordinary lives in adulthood, but prognosis depends on the severity of the initial pathology.
  • Children with mild forms often have a good prognosis, blending in with peers and leading full lives with a life expectancy similar to the general population.
  • As patients age, their growth rate slows, and differences between them and peers become less noticeable. Other physical features, such as enlarged tongue, may also become less apparent in adulthood.
  • However, even if a child no longer stands out from peers externally, ongoing medical supervision is necessary to detect dangerous complications early.
  • For children with severe BWS and multiple complications (including tumors, various physical anomalies, hypoglycemia), prognosis depends on the severity of complications and the effectiveness of treatment. The life expectancy of such patients is directly related to the quality of medical care received.