Beckwith-Wiedemann Syndrome

Types of Beckwith-Wiedemann Syndrome (BWS):

1. Classic BWS: This is the most common type, where individuals may show a combination of symptoms like enlarged organs and growth abnormalities.
2. Partial BWS: In this type, individuals may only exhibit some of the typical BWS features, making it a milder form of the syndrome.

Causes of Beckwith-Wiedemann Syndrome (BWS):

1. Genetic Mutations: BWS is primarily caused by changes in certain genes. These genetic mutations can occur spontaneously or be inherited from parents.
2. Chromosomal Abnormalities: Sometimes, BWS can be associated with abnormalities in the structure or number of chromosomes.
3. Imprinting Errors: BWS can also result from errors in the way specific genes are “imprinted” or marked for activity. These errors can lead to overgrowth.
4. Unknown Factors: In some cases, the exact cause of BWS remains unknown.

Genetics is the study of genes whereas epigenetics is the study of how those genes are turned on or off (gene expression). BWS results from various abnormalities affecting the proper expression of genes that control growth within a specific region of chromosome 11(11p15.5). This region is referred to as the BWS critical region.[rx]

Approximately 80% of people with BWS have no family history of this syndrome. For these people, BWS is usually caused by epigenetic changes that appear to occur randomly (sporadically). More rarely, BWS is caused by genetic changes that are passed down from a parent (inherited). Approximately 5-10% of patients have BWS due to a family history of the syndrome. About 14% of patients with BWS have an unknown cause for diagnosis?.[rx]

Everyone has two copies of every gene, one received from the father, and one received from the mother. In most people, both genes are “turned on” or active. However, some genes are “turned off” or preferentially silenced based upon which parent that gene came from (a process known as genomic imprinting). Genomic imprinting is controlled by marks on the DNA called methylation. Proper genomic imprinting is necessary for normal development and defective imprinting on chromosome 11 can lead to BWS. Several genes that control growth on chromosome 11 are imprinted, which means that the gene is only active from the mother’s chromosome or the father’s chromosome but not both.[rx]

Imprinted genes tend to be clustered or grouped together. Chromosome 11p15.5 has two imprinting cluster regions known as imprinting centers 1 and 2 (IC1 and IC2). Several specific imprinted genes are located in these regions. The improper imprinting of these two regions leads to the improper expression of the genes located within the regions, playing a role in the development of BWS. These genes include H19 (a gene that signals not to grow), IGF2 (insulin?-like growth factor II), KCNQ10T1 (LIT1) and CDKN1C (p57[KIP2]) (a gene that signals not to grow).[rx]

H19 is a long noncoding RNA thought to play a role in inhibiting growth. IGF2 is a growth factor. KCNQ10T1 is a noncoding RNA and CDKN1C is a cell cycle regulator and tumor suppressor. Researchers believe that the paternally expressed genes promote growth and that the maternally expressed genes act as tumor suppressor genes or inhibit growth. Normally, H19 and CDKN1C are expressed from the maternal chromosome and IGF2 and KCNQ1OT1 are expressed from the paternal chromosome. Improper methylation in the BWS critical region can lead to an imbalance of the “grow” and “don’t grow” signals, leading to overgrowth.[rx]

Gain of methylation (hypermethylation) at imprinting center 1 (IC1 GOM) occurs in about 5% of patients with BWS. This leads to decreased H19 expression and increased IGF2 expression.

Imprinting center 2 (IC2) is associated with KvDMR, a chemical switch found on the KCNQ1 gene. Loss of methylation (hypomethylation) at KvDMR of imprinting center 2 (IC2 LOM) occurs in about 50% of people with BWS. This leads to increased KCNQ10T1 (long QT intronic transcript 1 [LIT1]) expression and decreased CDKN1C expression.[rx]

Imprinting errors may also be caused by a chromosomal abnormality known as uniparental disomy (UPD). UPD occurs when a person receives both copies of a chromosome (or part of a chromosome) from one parent instead of receiving one copy from each parent. Approximately 20% of people with BWS have UPD. In BWS, both copies of chromosome 11 are received from the father (paternal uniparental disomy (pUPD)). As a result, there are too many active paternally expressed genes (IGF2) in this region and not enough maternally expressed genes (H19, CDKN1C). Uniparental paternal disomy occurs after fertilization, and therefore the risk of recurrence is extremely low.[rx]

Mosaic genome-wide paternal uniparental isodisomy (GWpUPD) occurs in about 10% of BWS due to pUPD (approximately 2% of all patients with BWS). In the case of GWpUPD, every chromosome is inherited from the father in the cells that carries the abnormality, instead of just chromosome 11 as in pUPD. GWpUPD is associated with a greater tumor risk. The severity of GWpUPD varies according to the number of cells affected and where the affected cells are located within the patient.

Changes (variants or mutations) of the CDKN1C gene have been detected in some individuals with BWS. The loss of proper expression or “underexpression” of the gene is thought to play an important role in causing the disorder. Approximately 5% of people with BWS are found to have variants of the CDKN1C gene. The variant is inherited in an autosomal dominant pattern, which means that only one copy of the changed gene is needed for the disorder to occur. However, CDKN1C is normally only maternally expressed, and therefore, children will only be affected (i.e., have BWS) if the variant is passed from the mother. Approximately 40% of individuals with a family history of BWS have variants of the CDKN1C gene. Variants in CDKN1C can also occur randomly without the mother carrying the variant (de novo). Patients with BWS due to CDKN1C changes have a 50% risk of passing the variant to their children.[rx]

Research has shown that small deletions (microdeletions) affecting imprinting center 1 (IC1) of chromosome 11p15.5 may be the cause of familial BWS in some people. Approximately 1-2% of patients with BWS have deletions involving 11p15.5. Microdeletions of the KCNQ10T1 (LIT1) gene have also been identified in some people with BWS. These microdeletions appear to cause BWS when inherited maternally; when inherited paternally, the disorder does not develop. Small duplications (microduplications), affecting imprinting center 1 (IC1) of chromosome 11p15.5 inherited from the father can also cause BWS. These microduplications can also occur randomly (de novo).

Approximately 2-4% of cases of BWS are due to various chromosomal abnormalities involving the 11p15.5 chromosomal region. This includes chromosomal inversions or rearrangements (translocations) or the presence of extra chromosomal material (duplications).[rx]

Phenotype genotype correlation
Researchers are investigating if specific causes of BWS are associated with specific symptoms (genotype-phenotype correlation). Research indicates that omphalocele and macroglossia are more common in individuals with defects of IC2 or a variant in the CDKN1C gene. Patients with pUPD are at a greater risk for lateralized overgrowth and hyperinsulinism. Individuals with defects of IC1 or pUPD appear to be at a greater risk of developing an associated tumor such as Wilms tumor. Patients with pUPD also have a greater risk of developing a liver tumor (hepatoblastoma). The different molecular types of BWS each carry a different tumor risk. More research is necessary to determine how the specific causes of BWS correlate with the various symptoms of the disorder[rx].

Symptoms of Beckwith-Wiedemann Syndrome (BWS):

1. Enlarged Organs: Affected individuals may have enlarged organs, such as the liver, kidneys, or tongue.
2. Overgrowth: Children with BWS often experience rapid and excessive growth, which can lead to a larger body size.
3. Abdominal Wall Defects: Some may have abdominal wall defects like an umbilical hernia or omphalocele, where abdominal organs protrude through the belly button.
4. Facial Features: BWS can result in certain facial features like an enlarged tongue and a wider-than-usual space between the eyes.
5. Low Blood Sugar: Babies with BWS may have episodes of low blood sugar (hypoglycemia?).
6. Increased Cancer Risk: There is an increased risk of certain cancers, such as Wilms tumor and hepatoblastoma, in individuals with BWS.
7. Kidney Abnormalities: Kidney abnormalities may be present, including enlarged or cystic kidneys.
8. Ear Creases or Pits: Some individuals may have creases or pits in their ears.
9. Limb Abnormalities: Rarely, BWS can lead to limb abnormalities.
10. Macroglossia: This term refers to an abnormally large tongue, which is a common feature in BWS.

Diagnostic Tests for Beckwith-Wiedemann Syndrome (BWS):

1. Genetic Testing: A blood or saliva sample is analyzed to check for genetic mutations associated with BWS.
2. Physical Examination: Doctors will look for physical signs and symptoms, such as enlarged organs or facial features.
3. Ultrasound?: Prenatal or postnatal ultrasounds can help detect organ abnormalities.
4. Alpha-Fetoprotein (AFP) Test: Elevated levels of AFP in the blood can be a sign of BWS.
5. Chromosome Analysis: This test examines the number and structure of chromosomes.
6. Biopsy?: In some cases, a tissue sample may be taken to diagnose associated tumors.
7. Imaging: X-rays or other imaging tests may be used to assess organ size and structure.
8. Clinical Evaluation: A thorough clinical evaluation by a medical team is crucial for a diagnosis?.

Treatments for Beckwith-Wiedemann Syndrome (BWS):

1. Monitoring: Regular check-ups and monitoring of organ size and overall health are essential.
2. Surgery: Surgical correction may be needed for abdominal wall defects or enlarged organs.
3. Hormone Therapy: In some cases, growth hormone therapy may be considered to manage overgrowth.
4. Managing Hypoglycemia?: For individuals with low blood sugar, frequent feedings or intravenous (IV) glucose may be necessary.
5. Cancer Screening?: Regular cancer screening? is essential to detect and treat tumors early if they develop.
6. Speech Therapy: If an enlarged tongue affects speech, speech therapy can help.
7. Psychosocial Support: Emotional and psychological support can be valuable for individuals and families dealing with BWS.

Drugs Related to Beckwith-Wiedemann Syndrome (BWS):

1. Growth Hormone: Growth hormone medications may be prescribed to manage excessive growth.
2. Glucose Solutions: In cases of hypoglycemia?, glucose solutions may be used to maintain blood sugar levels.
3. Anti-Cancer Medications: If cancerous tumors like Wilms tumor or hepatoblastoma develop, chemotherapy drugs may be needed.
4. Pain? Relief Medications: After surgical procedures, pain? relief medications may be prescribed.
5. Antibiotics: These may be necessary to prevent or treat infections, especially after surgery.

In newborns with BWS, regular monitoring of blood glucose levels should be performed to ensure prompt detection and treatment of hypoglycemia? in the immediate neonatal period. Although neonatal hypoglycemia is usually mild and temporary, its early detection and treatment is essential in preventing associated neurologic complications. Treatment measures may include the administration of intravenous glucose, frequent feedings, certain medications (e.g., diazoxide or octreotide) and/or surgical intervention in some cases.[rx]

In many infants with umbilical hernia, the defect may spontaneously disappear by the age of approximately one year. Surgery is usually not required unless an umbilical hernia becomes progressively larger, does not spontaneously resolve (e.g., by about three or four years of age) and/or is associated with certain complications. However, in newborns with an omphalocele, surgical repair of the defect is typically required shortly after birth.[rx]

Like other features associated with BWS, macroglossia can vary in severity. Patients with macroglossia are at an increased risk for obstructive sleep apnea, feeding difficulties, speech difficulties and potential jaw development issues. Patients with macroglossia require the support of a multidisciplinary team. They should undergo feeding evaluation and sleep studies in addition to consultations with plastic surgeons and pulmonologists if needed. Feeding difficulties caused by macroglossia may require the support of feeding specialists or dieticians. Treatment may include the use of specialized nipples or the temporary insertion of a nasogastric tube. Speech difficulties may require the support of speech therapy. A pulmonologist can evaluate the degree to which macroglossia affects a patient’s breathing and sleeping. A sleep study may be used to assess obstructive sleep apnea, airway obstruction, airway resistance, severe desaturation, sleep disordered breathing and snoring. Continuous positive airway pressure (CPAP) is a method used to support children with obstructive sleep apnea. Some patients may undergo tongue reduction surgery with the goal of improving breathing, feeding and jaw or dental malformations due to macroglossia. Patients with macroglossia should be followed closely by a multidisciplinary team.[rx]

Regular orthopedic evaluation is recommended for patients with lateralized overgrowth and an associated leg length difference. Some patients with significant lateralized overgrowth of the limbs may require shoe lifts and, in other patients, surgical correction may be needed.

Infants and patients with BWS should undergo regular abdominal and renal? ultrasounds, and measurement of serum alpha-fetoprotein levels as recommended to ensure early detection and treatment of certain malignancies that may occur in association with BWS (e.g., Wilms tumor, hepatoblastoma).[rx]

Alpha-fetoprotein (AFP) is a protein produced by the liver. AFP levels typically decline during infancy; however, AFP may be abnormally elevated in blood if certain tumors are present (hepatoblastoma). The trend in AFP levels over time should be followed in patients with BWS and normal AFP values for children with BWS are available to aid in interpretation of results. There have been recent discussions regarding the utility of AFP screening? in young children. While some suggest that the invasiveness of a regular blood draw may be stressful for many families, AFP has proven to be a useful early indicator for hepatoblastoma.[rx]

According to the United States-based guidelines, screening? is recommended for all patients with a clinical or molecular diagnosis? of BWS by AFP analysis and a full abdominal ultrasound? every three months until the 4th birthday (to screen for hepatoblastoma and Wilms tumor) followed by renal? ultrasounds every 3 months until 7th birthday (to screen for Wilms tumor). Additional screening by urine analysis and chest x-rays for neuroblastoma is recommended for patients with CDKN1C variants. Also, screening? for patients with BWS due to GWpUPD may extend beyond the 7th birthday.[rx]

If a tumor develops in association with BWS, the appropriate treatment measures vary depending on the specific tumor present, the stage and/or extent of disease and/or other factors. Treatment methods may include surgery (for example, nephron-sparing kidney resection in the case of a Wilms tumor), use of certain anticancer drugs (chemotherapy), radiation therapy and/or other measures. (For more information on Wilms tumor, choose “Wilms” as your search term in the Rare Disease Database.)[rx]

Patients with cardiac, gastrointestinal and renal? abnormalities may require certain medications, surgery or other medical interventions. These patients should be referred to appropriate specialists.

Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

In summary, Beckwith-Wiedemann Syndrome is a rare genetic disorder with various types, caused by genetic mutations, imprinting errors, or chromosomal abnormalities. It leads to symptoms like overgrowth, enlarged organs, and an increased risk of certain cancers. Diagnosis? involves genetic testing, physical examinations, and other tests. Treatment includes monitoring, surgery, hormone therapy, and supportive care. In some cases, drugs like growth hormone or chemotherapy may be used. Early detection and comprehensive care are vital for managing BWS effectively.[rx]

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. Thank you for giving your valuable time to read the article.