Beckwith-Wiedemann Syndrome (BWS) is a rare congenital disorder that causes abnormal growth in infants and children. It involves changes in genes on chromosome 11p15, affecting how cells divide and grow. These genetic changes disrupt normal growth regulation, which is why children with BWS often present with a large tongue, one-sided body overgrowth, and a higher risk of childhood tumors. Therefore, it’s essential to recognize the clinical clues and understand the clinical implications of this syndrome, particularly in pediatric and oncology settings.

What causes Beckwith-Wiedemann Syndrome?

Beckwith-Wiedemann Syndrome (BWS) is caused by changes in imprinted genes. These are special genes in which only one parental copy (either from the mother or the father) is active while the other is switched off.

In BWS, the body fails to regulate which copy of an imprinted gene should be active, leading to an imbalance in gene expression. This imbalance disrupts the normal growth patterns, causing excessive growth before and after birth. To understand how these genetic changes affect the body, let’s discuss the pathophysiology behind BWS.

Pathophysiology of Beckwith-Wiedemann Syndrome:

The key changes in BWS occur on chromosome 11, particularly in the region designated as 11p15.5. This region regulates how certain growth-related genes are turned on or off.
It contains two main imprinting control areas, IC1 and IC2, which act like genetic switches.¹

Imprinting Center 1 (IC1): IC1 controls the IGF2 (Insulin-like Growth Factor 2) and H19 genes. IGF2 is a growth-promoting gene, while H19 is a growth-inhibiting gene.
In Beckwith-Wiedemann Syndrome, an abnormality at IC1 causes the IGF2 gene to become overactive, while the H19 gene is silenced, leading to uncontrolled cell growth and a higher risk of developing tumors.
Imprinting Center 2 (IC2): Under normal conditions, the IC2 region on chromosome 11p15.5 acts as a switch that activates CDKN1C and maintains normal growth. However, in BWS, CDKN1C gets silenced, resulting in uncontrolled tissue development in the developing fetus.

Genetic & Epigenetic Mechanisms in BWS:

Five main genetic and epigenetic changes cause BWS. Each one affects the 11p15.5 region, but in different ways:²

Mechanism	What Happens	Frequency
Loss of methylation at IC2 (KCNQ1OT1)	CDKN1C is silenced → Overgrowth	~50–60%
Paternal Uniparental Disomy (UPD) of 11p15	Two paternal copies → Increased IGF while decreased CDKN1C	~20–25%
Gain of methylation at IC1	Overexpression of IGF2	~5–10%
CDKN1C gene mutations	Brakes on growth are genetically broken	~5%
Chromosomal abnormalities (duplications, translocations)	Usually inherited	<1%

How common is it?

BWS is a rare congenital condition that occurs in approximately 1 in 10,000 live births. Milder cases of BWS often remain undiagnosed, suggesting that the actual incidence rate might be higher. BWS affects all ethnic groups equally, with no gender differences observed.³

Multiple studies suggest that children conceived through Assisted Reproductive Technologies (ART) such as In vitro fertilization (IVF) or Intracytoplasmic sperm injection (ICSI) have a significantly higher risk of developing BWS. The risk is estimated to be 3 to 10 times higher than in naturally conceived pregnancies.⁴

Symptoms of Beckwith-Wiedemann Syndrome

Common physical signs of Beckwith-Wiedemann syndrome — Example of findings in Beckwith-Wiedemann Syndrome. Reproduced from Wang, R., Xiao, Y., Li, D., Hu, H., Li, X., Ge, T., Yu, R., Wang, Y., & Zhang, T. (2020). *Clinical and molecular features of children with Beckwith-Wiedemann syndrome in China: a single-center retrospective cohort study*. *BMC Pediatrics*, 20, Article 187. https://doi.org/10.1186/s12887-020-02109-3 — licensed under **CC BY 4.0**.

Children with BWS present a wide range of clinical features varying significantly from child to child. Some babies may show mild signs, while others may have multiple and more obvious signs.
Common signs and symptoms of Beckwith-Wiedemann syndrome are:⁵

Macrosomia (Unusually Large Size or Weight):

Children with BWS usually grow faster than normal during pregnancy and after they’re born (Macrosomia). Overgrowth affects both weight and length, which is often noticeable in the uterus during pregnancy. Most mothers report increased amniotic fluid (polyhydramnios) during pregnancy.

Macroglossia (Enlarged Tongue):

BWS causes an abnormally enlarged tongue in babies. This condition causes difficulty in feeding, breathing problems, drooling, and even speech difficulties later in life. In severe cases, the tongue may even protrude out of the mouth.

Hemihyperplasia (Asymmetrical Growth of one side of the Body):

While the majority of babies grow large symmetrically, some show uneven growth, where one side of the body is noticeably larger than the other. This occurs due to the localized overexpression of growth-promoting genes in those tissues. The difference, whether subtle or pronounced, increases with age.

Organomegaly (Enlargement of Internal Organs):

BWS patients may also have oversized abdominal organs, especially the liver, kidneys, and pancreas. Increased organ size, particularly of the pancreas, may worsen blood sugar regulation. This also explains why many babies with BWS experience hypoglycemia right after birth.

Neonatal Hypoglycemia:

About 30-50% of the babies with BWS have neonatal hypoglycemia within the first few days of their life. Scientists believe that feeding difficulties resulting from macroglossia and excessive insulin release from an enlarged pancreas may be the cause. It’s a serious complication that can cause brain injury if not treated in time.⁶

Abdominal Wall Defects:

In BWS, the fetus grows rapidly, increasing pressure inside the mother’s uterus. This may lead to:

Omphalocele: A sac-like herniation of abdominal contents through the umbilicus.
Umbilical hernia: A less severe protrusion around the belly button.
Diastasis recti: A separation of the abdominal muscles without herniation.

Increased Risk of Embryonal Tumors:

The same overactive genes responsible for rapid growth in BWS also raise the risk of childhood tumors. These tumors develop in roughly 5–10% of cases and include cancers of the kidney or liver.⁷

Ear Creases or Pits:

Some infants with BWS have unusual ear shapes, like,

Creases or folds in the earlobe
Small pits or dimples in front of the ear

These features don’t functionally impair, but can be helpful clues for diagnosis, especially when other signs are mild.

Genital or Renal Anomalies:

These include undescended testes or kidney swelling.

How is Beckwith-Wiedemann Syndrome diagnosed?

Diagnosis of Beckwith-Wiedemann Syndrome involves the combination of clinical evaluation, genetic testing, and imaging studies. Since BWS presents with a wide range of symptoms, diagnoses can sometimes be difficult.

Clinical Evaluation:

Clinical evaluation is the first step in the diagnosis. Many features of BWS are visible shortly after birth, which can help neonatologists and pediatricians to make an initial suspicion.

Clinical Scoring System (International Consensus Criteria)

As symptoms vary from patient to patient, doctors can’t rely solely on clinical features for diagnosis. Therefore, scientists developed clinical scoring systems for BWS to make diagnoses more accurate and consistent. The traditionally followed scoring system deems two major findings or one major and two minor findings sufficient to diagnose BWS.
But a more practical and objective scoring system is that of Brioude, which involves two types of features, i.e, cardinal and suggestive:⁸

Cardinal Features: Cardinal features are the key characteristics, most commonly seen in a BWS. These include macroglossia, omphalocele, bilateral Wilms tumors, and lateralized overgrowth. Each cardinal feature contains 2 points.
Suggestive Features: Suggestive features are the less specific signs or findings that may point towards a diagnosis of BWS, but are not strong enough on their own to confirm it. Each suggestive feature has 1 point. Neonatal hypoglycemia, ear creases/ pits, umbilical hernia, and nephromegaly are some suggestive features of BWS.

If your total score is ≥4 (with at least one cardinal feature), your doctor will diagnose BWS even without a genetic test. On the other hand, a score of 2-3 suggests genetic testing, whereas a score below 2 means BWS is unlikely, and your doctor might not ask you to undergo a genetic test.

Genetic & Epigenetic Testing:

Once doctors suspect BWS based on clinical signs, the next step is to confirm it with molecular genetic testing. Molecular testing helps in genetic counseling and assessing the tumor risk. Common molecular tests are:⁹

Methylation-Specific Testing (MS-MLPA): This is the first-line investigation used to confirm a diagnosis of BWS. The majority of BWS patients have abnormal methylation on the imprinting control regions IC1 and IC2 on chromosome 11p15, resulting in too much or too little gene activity, respectively. By examining whether certain genes are properly on or off, this test helps identify abnormal methylation and, hence, diagnose BWS.

UPD Testing (Uniparental Disomy Testing): UPD testing identifies whether both copies of 11p15 came from the father. In physiological circumstances, a child should receive one copy of 11p15 from the mother and one from the father. But in BWS, both copies come from the father, disrupting the normal balance of gene expression, especially in the imprinted genes. UPD testing helps detect this and hence diagnose 20% of BWS cases that have paternal uniparental disomy (pUPD) of chromosome 11p15.
CDKN1C Sequencing: There are scenarios when the methylation test doesn’t yield a positive result, despite high clinical suspicion and a positive family history. In such cases, this CDKN1C Sequencing comes into play. It detects the point mutations in the CDKN1C gene and helps diagnose the 10-15% BWS cases with this genetic defect.

Chromosomal Microarray/Karyotyping: This test is used to detect duplications, deletions, or rearrangements in the 11p15 region of the chromosome.

(Note: Interestingly, scientists also say that a negative genetic test doesn’t fully rule out BWS. That’s because some children may have mosaicism, where only certain cells carry the mutation. In these situations, a clinical diagnosis remains important.)

Imaging & Laboratory Tests:

Although imaging and lab tests can’t confirm BWS, they play a key role in detecting complications and assessing the risk of tumors.

Abdominal ultrasound – to check for organomegaly or Wilms’ tumor
Liver ultrasound and AFP levels – for hepatoblastoma screening
Echocardiography – in newborns with suspected cardiac anomalies
Brain or skeletal imaging – if developmental issues or asymmetry are severe

Reducing Beckwith-Wiedemann Syndrome Risk in Future Pregnancies

Yes, you can reduce the risk of BWS in future pregnancies, particularly where inherited mutations are involved.¹⁰

Families with Sporadic Methylation Errors/ UPD require no special interventions for future pregnancies because their rate of recurrence is quite low, i.e, less than 1%.
Maternal CDKN1C mutations/11p15 chromosomal rearrangement: The recurrence in this case is 50%. Therefore, genetic counseling is strongly recommended. It’s important to offer carrier testing to the mother, and in some situations, the father may also be tested.

Prenatal Testing Options for Future Pregnancies:

If you have had a child with BWS and you want to explore prenatal diagnostic options in future pregnancies, you can consider the following labs:¹¹

First-Trimester Testing

Chorionic Villus Sampling (CVS) at 11–13 weeks
Test for CDKN1C mutations or methylation abnormalities (based on the previous child’s results)

Second-Trimester Testing

Amniocentesis at 15–18 weeks
Fetal DNA is analyzed for known mutations or epigenetic changes

Ultrasound Monitoring

To look for:

Fetal overgrowth
Macroglossia
Omphalocele or organomegaly
Polyhydramnios

Although ultrasound alone doesn’t diagnose BWS, it can raise suspicion and guide further testing.

Treatment Options for Beckwith-Wiedemann Syndrome

Early diagnosis, especially prenatal, can greatly influence when and how BWS should be treated. While there’s currently no cure for Beckwith-Wiedemann Syndrome, we can do a lot to manage symptoms and prevent complications. That’s why a multidisciplinary team approach is essential for providing proper care.¹²

Early Diagnosis & Delivery Planning:

If BWS is suspected during pregnancy, delivery should take place at a specialized center. These centers should have neonatal and surgical teams ready to provide immediate care and manage potential complications after birth.

Management of Neonatal Hypoglycemia:

Hypoglycemia in neonates is an emergency that needs prompt and aggressive management; otherwise, neurological injury is inevitable. Healthcare providers should closely monitor the blood glucose levels of the newborn, as persistent hypoglycemia is common in babies with BWS.

Start with intravenous glucose. If hyperinsulinism is severe, consider drugs that inhibit the release of insulin, such as diazoxide and octreotide.
In case of unresponsiveness to these drugs, your surgeon may consider a partial pancreatectomy to halt insulin release, resulting in neurological damage from hypoglycemia.

Surgical Management:

Surgical intervention helps correct the structural and functional abnormalities seen in BWS, for example:

Macroglossia (Enlarged Tongue) While some children with mild macroglossia improve over time without needing surgery, others may need a tongue reduction procedure, particularly when the enlarged tongue causes breathing or speech problems. This surgery is ideally performed between three to twelve months of age.¹³ ¹⁴
Abdominal Wall Defects: Milder cases of omphalocele or umbilical hernia may resolve on their own, so your healthcare provider might just suggest wait and watch. But in severe cases, surgical correction of omphalocele may be the only option.
For hemihyperplasia, orthopedic monitoring and management may be required.

Management of Cardiac & Renal Anomalies:

Doctors usually do a baseline heart ultrasound (echocardiogram) to check for associated cardiac abnormalities such as congenital heart disease and cardiomegaly, and plan treatment accordingly. Doctors may consider pediatric renal ultrasound and renal function tests to detect kidney-related issues.

Multidisciplinary Team Care:

Remember that effective BWS management involves coordinated care from:

Pediatricians
Geneticists
Endocrinologists
Craniofacial and feeding specialists
Oncologists
Orthopedic surgeons
Psychologists

The International Consensus Statement on Beckwith–Wiedemann Syndrome highlights the importance of personalized, long-term care managed by a primary doctor who coordinates across specialties.¹⁵

Additionally, there should be regular assessments for growth abnormalities, speech and motor delays, early puberty, or asymmetrical overgrowth. Also, doctors should educate family members about the risk of recurrence and prenatal diagnosis options.

Cancer Risk, Screening & Long-Term Follow-Up:

Children with BWS are at a higher risk of embryonal tumors, mainly:¹⁶

Tumor Type	Frequency in BWS	Typical Age of Onset
Wilms’ Tumor (kidney cancer)	~5%	1 to 4 years
Hepatoblastoma (liver tumor)	~1–2%	<2 years
Neuroblastoma, Rhabdomyosarcoma	Rare	Varies

But not all children with BWS have the same cancer risk. It depends on the type of underlying genetic or epigenetic change, for example:

Genetic Subtype	Estimated Tumor Risk	Common Tumor Types
IC1 gain of methylation	22–28%	Wilms tumor
Paternal UPD (11p15)	16–17%	Wilms’ tumor, hepatoblastoma
CDKN1C mutation	6.9–8.8%	Variable
IC2 loss of methylation	2.5–3.1%	Rare (very low risk)

This helps decide how often and how long a child needs tumor screening.

Tumor Screening Protocols

Regular screening can catch tumors early, when they’re easier to treat. Tumor Screening Protocols as per the American Association for Cancer Research Guidelines suggest:

Abdominal ultrasound every 3 months until age 7–8
Alpha-fetoprotein (AFP) levels every 6 weeks until age 4 (for hepatoblastoma)¹⁷

Differential Diagnosis

The following overgrowth syndromes resemble BWS in clinical picture:

Isolated Hemihyperplasia:

It manifests as an asymmetric limb or facial growth, in the absence of other BWS features such as macroglossia, abdominal wall defects, etc. Doctors diagnose it when the family history is negative and the methylation test also yields a negative result.

Sotos Syndrome or Cerebral Gigantism:

It’s a genetic disorder characterized by overgrowth in childhood, learning disabilities, and typical facial features. The underlying genetic change is an NSD1 mutation.

Child with facial features of syndrome — Characteristic facial features in Sotos syndrome. Image Courtesy: Wikimedia Commons, under CC license

Simpson-Golabi-Behmel Syndrome (SGBS):

It’s an X-linked recessive overgrowth disorder. It’s similar to BWS in terms of the overgrowth features, but differs regarding coarse facial features, digit and nipple abnormalities. The underlying mutation affects the GPC3 gene.

Pearlman Syndrome:

It’s yet another overgrowth syndrome that differs from BWS with severe hypertonia, nephroblastomatosis, and characteristic deep-set eyes. DIS3L2 gene testing helps rule it out.

Prognosis & Life Expectancy of Beckwith-Wiedemann Syndrome

Prognosis with BWS is generally good, especially when the condition is diagnosed early and managed properly.¹⁸

With appropriate monitoring, surgical care, and early cancer surveillance, most children with BWS have a normal life expectancy. There is no evidence that BWS shortens life unless the complications, like cancer, neonatal hypoglycemia, remain untreated.

Long-Term Follow-Up:

Once the high-risk period for cancer passes, the focus shifts to monitoring long-term growth and developmental outcomes:

Those treated for tumors need long-term follow-up with oncology.
Children with severe hypoglycemia, macroglossia, or surgical complications may need endocrinology or surgical follow-up.
Developmental assessments are recommended if early complications have affected growth or learning.

Conclusion

Beckwith-Wiedemann Syndrome (BWS) is a rare and complex genetic disorder caused by imprinting defects. Because the signs vary from child to child, an accurate diagnosis relies on both clinical scoring and genetic testing. With timely diagnosis, personalized care, and regular tumor screening, most children grow up healthy and lead normal lives. Early care and family education can make a lasting difference for BWS patients.

Refrences

1
Borjas Mendoza PA, Daley SF, Mendez MD. Beckwith-Wiedemann Syndrome. [Updated 2024 Jan 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK558993/
2
Soejima, H., & Higashimoto, K. (2013). Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders. Journal of human genetics, 58(7), 402–409.
3
Duffy, K. A., Sajorda, B. J., Yu, A. C., Hathaway, E. R., Grand, K. L., Deardorff, M. A., & Kalish, J. M. (2019). Beckwith-Wiedemann Syndrome in Diverse Populations. American Journal of Medical Genetics. Part A, 179(4), 525. https://doi.org/10.1002/ajmg.a.61053
4
Mussa, A., Molinatto, C., Cerrato, F., Palumbo, O., Carella, M., Baldassarre, G., Carli, D., Peris, C., Riccio, A., & Ferrero, G. B. (2017). Assisted Reproductive Techniques and Risk of Beckwith-Wiedemann Syndrome. Pediatrics, 140(1), e20164311. https://doi.org/10.1542/peds.2016-4311
5
Shuman C, Kalish JM, Weksberg R. Beckwith-Wiedemann Syndrome. 2000 Mar 3 [Updated 2023 Sep 21]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: Beckwith-Wiedemann Syndrome – GeneReviews® – NCBI Bookshelf
6
Shuman C, Kalish JM, Weksberg R. Beckwith-Wiedemann Syndrome. 2000 Mar 3 [Updated 2023 Sep 21]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1394/
7
MacFarland, S. P., Duffy, K. A., Bhatti, T. R., Bagatell, R., Balamuth, N. J., Brodeur, G. M., Ganguly, A., Mattei, P. A., Surrey, L. F., Balis, F. M., & Kalish, J. M. (2018). Diagnosis of Beckwith-Wiedemann syndrome in children presenting with Wilms’ tumor. Pediatric blood & cancer, 65(10), e27296. https://doi.org/10.1002/pbc.27296
8
Brioude, F., Kalish, J. M., Mussa, A., Foster, A. C., Bliek, J., Ferrero, G. B., Boonen, S. E., Cole, T., Baker, R., Bertoletti, M., Cocchi, G., Coze, C., De Pellegrin, M., Hussain, K., Ibrahim, A., Kilby, M. D., Krajewska-Walasek, M., Kratz, C. P., Ladusans, E. J., Lapunzina, P., … Maher, E. R. (2018). Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nature Reviews. Endocrinology, 14(4), 229–249. https://doi.org/10.1038/nrendo.2017.166
9
Ibrahim, A., Kirby, G., Hardy, C., Dias, R. P., Tee, L., Lim, D., Berg, J., MacDonald, F., Nightingale, P., & Maher, E. R. (2014). Methylation analysis and diagnostics of Beckwith-Wiedemann syndrome in 1,000 subjects. Clinical epigenetics, 6(1), 11. https://doi.org/10.1186/1868-7083-6-11
10
Weksberg, R., Shuman, C., & Beckwith, J. B. (2010). Beckwith-Wiedemann syndrome. European journal of human genetics: EJHG, 18(1), 8–14. https://doi.org/10.1038/ejhg.2009.106
11
Gaspar, V., Branco, M., Galhano, E., & Ramos, F. (2022). Ultrasound and molecular prenatal diagnosis of Beckwith-Wiedemann syndrome: Two case reports. Radiology Case Reports, 17(12), 4914. https://doi.org/10.1016/j.radcr.2022.09.066
12
Wang, K. H., Kupa, J., Duffy, K. A., & Kalish, J. M. (2020). Diagnosis and Management of Beckwith-Wiedemann Syndrome. Frontiers in pediatrics, 7, 562. https://doi.org/10.3389/fped.2019.00562
13
Romeo, D. J., Wagner, C. S., Banala, M., George, A. M., Massenburg, B. B., Wu, M., Ng, J. J., Cielo, C. M., Kalish, J. M., & Taylor, J. A. (2025). Conservative management of macroglossia in Beckwith-Wiedemann Syndrome. PEDIATRICS. https://doi.org/10.1542/peds.2024-068618
14
Kittur, M. A., Padgett, J., & Drake, D. (2013). Management of macroglossia in Beckwith-Wiedemann syndrome. The British journal of oral & maxillofacial surgery, 51(1), e6–e8. https://doi.org/10.1016/j.bjoms.2012.01.015
15
Brioude, F., Kalish, J. M., Mussa, A., Foster, A. C., Bliek, J., Ferrero, G. B., Boonen, S. E., Cole, T., Baker, R., Bertoletti, M., Cocchi, G., Coze, C., De Pellegrin, M., Hussain, K., Ibrahim, A., Kilby, M. D., Kratz, C. P., Ladusans, E. J., Lapunzina, P., . . . Maher, E. R. (2018). Clinical and molecular diagnosis, screening and management of Beckwith–Wiedemann syndrome: An international consensus statement. Nature Reviews Endocrinology, 14(4), 229-249. https://doi.org/10.1038/nrendo.2017.166
16
Mussa, A., Molinatto, C., Baldassarre, G., Riberi, E., Russo, S., Larizza, L., Riccio, A., & Ferrero, G. B. (2016). Cancer Risk in Beckwith-Wiedemann Syndrome: A Systematic Review and Meta-Analysis Outlining a Novel (Epi) Genotype-Specific Histotype Targeted Screening Protocol. The Journal of Pediatrics, 176, 142–149.e1.
17
Kalish, J. M., Becktell, K. D., Bougeard, G., Brodeur, G. M., Diller, L. R., Doria, A. S., Hansford, J. R., Klein, S. D., Kohlmann, W. K., Kratz, C. P., MacFarland, S. P., Pajtler, K. W., Rednam, S. P., Schienda, J., States, L. J., Villani, A., Weksberg, R., Zelley, K., Tomlinson, G. E., & Brzezinski, J. J. (2024). Update on surveillance for Wilms tumor and hepatoblastoma in Beckwith-Wiedemann Syndrome and other predisposition syndromes. Clinical Cancer Research. https://doi.org/10.1158/1078-0432.ccr-24-2100
18
Porteus, M. H., Narkool, P., Neuberg, D., Guthrie, K., Breslow, N., Green, D. M., & Diller, L. (2000). Characteristics and outcome of children with Beckwith-Wiedemann syndrome and Wilms’ tumor: a report from the National Wilms Tumor Study Group. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 18(10), 2026–2031. https://doi.org/10.1200/JCO.2000.18.10.2026

Beckwith-Wiedemann Syndrome: Causes, Signs & Diagnosis

In this Article [hide]