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PubMed This is a summary of 19 peer-reviewed journal articles Updated
Medical Genetics

The Genetics of BWS: Switches and Subtypes

At a Glance

Beckwith-Wiedemann Syndrome (BWS) has four main genetic subtypes: IC2-LoM, pUPD11, IC1-GoM, and CDKN1C. Identifying your child's exact subtype is essential because it determines their specific risk for childhood cancers and dictates their customized tumor screening schedule.

Understanding the genetics of Beckwith-Wiedemann Syndrome (BWS) is the key to managing your child’s health. While the terminology can be complex, it helps to think of it like a set of electrical circuits and switches that control growth.

The 11p15.5 Region and Imprinting

All of the “blueprints” for BWS are located in a specific area of chromosome 11 called the 11p15.5 region [1]. Inside this region, genes are controlled by a process called genomic imprinting [2].

In a typical child, certain genes have “on/off” switches based on which parent they came from [2][3]. For example, a growth-promoting gene might be “on” from the father but “off” from the mother. In BWS, these switches are set incorrectly—too many growth genes are “on” or too many growth-restricting genes are “off”—leading to the physical features of the syndrome [4][5].

The Four Main Molecular Subtypes

Your child’s “subtype” is determined by which “switch” is broken. This is the most important information for their medical team because it dictates their specific cancer risk and screening schedule [6][7].

Subtype Summary Table

Subtype Frequency Physical Features Tumor Risk Level Primary Tumor Risks Routine AFP Screening?
IC2-LoM ~50% Macroglossia, Abdominal wall defects Lowest (2.5%) Hepatoblastoma (rare) Generally not recommended
pUPD11 ~20% Lateralized overgrowth, Severe hypoglycemia High (~14-16%) Wilms tumor, Hepatoblastoma Yes
IC1-GoM ~5-10% Extreme macrosomia, Enlarged organs Highest (~28%) Wilms tumor Generally not recommended
CDKN1C ~5% Omphalocele Moderate (~7-9%) Neuroblastoma No (Requires urine screening)

1. IC2-LoM (Loss of Methylation)

This is the most common cause of BWS, affecting about 50% of cases [5].

  • Physical Features: Often associated with macroglossia (large tongue) and abdominal wall defects, but these children are less likely to have macrosomia (large body size) [8][9].
  • Cancer Risk: Generally considered the lowest risk group for tumors (about 2.5%) [10][11].

2. pUPD11 (Paternal Uniparental Disomy)

This happens when a child inherits two copies of this region from their father and none from their mother [12].

  • Physical Features: Very likely to have lateralized overgrowth (one side of the body larger than the other) and severe low blood sugar at birth [13][14].
  • Cancer Risk: Carries a higher risk for several tumors, including Wilms tumor (kidney) and hepatoblastoma (liver) [10][13].

3. IC1-GoM (Gain of Methylation)

In this subtype, a growth-promoting switch is stuck in the “on” position [5].

  • Physical Features: Often results in extreme macrosomia (being very large at birth) and enlarged internal organs like the liver or kidneys [8][9].
  • Cancer Risk: This group has the highest risk for Wilms tumor (up to 22.8% to 28%) [10][15].

4. CDKN1C Mutations

This is a change in a specific gene that normally acts as a “brake” on growth [16].

  • Physical Features: Often associated with an omphalocele (abdominal wall defect) but less likely to have overgrowth [8].
  • Cancer Risk: These children have a unique risk for neuroblastoma (a type of nerve tissue tumor) but a very low risk for kidney or liver tumors [10][17].

Why Subtypes Matter for Surveillance

Because the risks vary so much, your doctor will tailor your child’s surveillance (screening) protocol [7][18]. For example, a child with IC1-GoM will need very frequent kidney ultrasounds, while a child with pUPD11 will also need regular blood tests (AFP) to watch for liver tumors [10][19]. Knowing your child’s subtype allows the medical team to focus on the most likely risks, providing the best protection while avoiding unnecessary tests where the risk is low [6].

Common questions in this guide

What are the four main genetic subtypes of Beckwith-Wiedemann Syndrome?
The four main molecular subtypes of BWS are IC2-LoM, pUPD11, IC1-GoM, and CDKN1C mutations. Each subtype involves a different genetic change on chromosome 11 and causes its own distinct physical features and tumor risk profiles.
Why is it important to know my child's specific BWS subtype?
Knowing your child's specific BWS subtype is crucial because it determines their exact risk for developing certain childhood cancers. This allows your medical team to create a customized tumor screening schedule that focuses on their highest risks while avoiding unnecessary tests.
Which BWS subtype has the highest risk for developing tumors?
Children with the IC1-GoM subtype have the highest overall risk for tumors, particularly Wilms tumor, with a risk level up to 28 percent. In contrast, the IC2-LoM subtype is the most common but carries the lowest tumor risk at around 2.5 percent.
Does my child's BWS subtype explain their low blood sugar at birth?
Yes, certain genetic subtypes are more closely linked to severe hypoglycemia at birth. Specifically, children with the pUPD11 subtype are very likely to experience severe low blood sugar alongside lateralized overgrowth.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Which of the four main molecular subtypes (IC1-GoM, IC2-LoM, pUPD11, or CDKN1C) does my child have?
  2. 2.Based on my child's specific subtype, what is their exact risk for Wilms tumor versus hepatoblastoma?
  3. 3.Should we be screening for neuroblastoma, or is that only for children with the CDKN1C subtype?
  4. 4.How does my child's subtype influence the frequency of their ultrasound and AFP blood tests?
  5. 5.Does my child's genetic subtype explain why they did (or did not) have severe low blood sugar after birth?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (19)
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    Investigation of (epi)genotype causes and follow-up manifestations in the patients with classical and atypical phenotype of Beckwith-Wiedemann spectrum.

    Tüysüz B, Güneş N, Geyik F, et al.

    American journal of medical genetics. Part A 2021; (185(6)):1721-1731 doi:10.1002/ajmg.a.62158.

    PMID: 33704912
  2. 2

    Concurrent Hepatoblastoma and Wilms Tumor Leading to Diagnosis of Beckwith-Wiedemann Syndrome.

    Wolfe DM, Webster Carrion A, Masukhani MM, et al.

    Journal of pediatric hematology/oncology 2023; (45(4)):e525-e529 doi:10.1097/MPH.0000000000002593.

    PMID: 36730589
  3. 3

    (Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome: a paradigm for genomic medicine.

    Mussa A, Russo S, Larizza L, et al.

    Clinical genetics 2016; (89(4)):403-415 doi:10.1111/cge.12635.

    PMID: 26138266
  4. 4

    Beckwith-Wiedemann syndrome: clinical and etiopathogenic aspects of a model genomic imprinting entity.

    Cammarata-Scalisi F, Avendaño A, Stock F, et al.

    Archivos argentinos de pediatria 2018; (116(5)):368-373 doi:10.5546/aap.2018.eng.368.

    PMID: 30204990
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    Disruption of KCNQ1 prevents methylation of the ICR2 and supports the hypothesis that its transcription is necessary for imprint establishment.

    Beygo J, Bürger J, Strom TM, et al.

    European journal of human genetics : EJHG 2019; (27(6)):903-908 doi:10.1038/s41431-019-0365-x.

    PMID: 30778172
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    Molecular Basis of Beckwith-Wiedemann Syndrome Spectrum with Associated Tumors and Consequences for Clinical Practice.

    Eggermann T, Maher ER, Kratz CP, Prawitt D

    Cancers 2022; (14(13)) doi:10.3390/cancers14133083.

    PMID: 35804856
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    [Beckwith-Wiedemann Syndrome (BWS) Current Status of Diagnosis and Clinical Management: Summary of the First International Consensus Statement].

    Elbracht M, Prawitt D, Nemetschek R, et al.

    Klinische Padiatrie 2018; (230(3)):151-159 doi:10.1055/a-0591-9479.

    PMID: 29660755
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    Fetal growth patterns in Beckwith-Wiedemann syndrome.

    Mussa A, Russo S, de Crescenzo A, et al.

    Clinical genetics 2016; (90(1)):21-7 doi:10.1111/cge.12759.

    PMID: 26857110
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    (Epi)genotype-phenotype correlations of Beckwith-Wiedemann syndrome in China.

    Lan D, Zhang S, Li J, et al.

    Italian journal of pediatrics 2025; (51(1)):276 doi:10.1186/s13052-025-02122-4.

    PMID: 41024278
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    Cancer Risk in Beckwith-Wiedemann Syndrome: A Systematic Review and Meta-Analysis Outlining a Novel (Epi)Genotype Specific Histotype Targeted Screening Protocol.

    Mussa A, Molinatto C, Baldassarre G, et al.

    The Journal of pediatrics 2016; (176()):142-149.e1.

    PMID: 27372391
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    Beckwith-Wiedemann syndrome: Clinical, histopathological and molecular study of two Tunisian patients and review of literature.

    Sassi H, Elaribi Y, Jilani H, et al.

    Molecular genetics & genomic medicine 2021; (9(10)):e1796 doi:10.1002/mgg3.1796.

    PMID: 34510813
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    Imprinted disorders and growth.

    Giabicani É, Brioude F, Le Bouc Y, Netchine I

    Annales d'endocrinologie 2017; (78(2)):112-113 doi:10.1016/j.ando.2017.04.010.

    PMID: 28478949
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    Cancer incidence and spectrum among children with genetically confirmed Beckwith-Wiedemann spectrum in Germany: a retrospective cohort study.

    Cöktü S, Spix C, Kaiser M, et al.

    British journal of cancer 2020; (123(4)):619-623 doi:10.1038/s41416-020-0911-x.

    PMID: 32451468
  14. 14

    Determinants of Hyperinsulinism Severity in Children with Beckwith-Wiedemann Syndrome.

    George AM, Viswanathan A, Sussman JH, et al.

    The Journal of clinical endocrinology and metabolism 2026; doi:10.1210/clinem/dgag053.

    PMID: 41655234
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    Phenotype, cancer risk, and surveillance in Beckwith-Wiedemann syndrome depending on molecular genetic subgroups.

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    American journal of medical genetics. Part A 2016; (170(9)):2248-60 doi:10.1002/ajmg.a.37801.

    PMID: 27419809
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    CDKN1C -Related Beckwith-Wiedemann Syndrome: First Patient from India.

    Arora V, Takkar A, Dubey S, et al.

    Journal of pediatric genetics 2024; (13(4)):330-334 doi:10.1055/s-0043-1764126.

    PMID: 39502854
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    Expanded phenotype and cancer risk in patients with Beckwith-Wiedemann spectrum caused by CDKN1C variants.

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    American journal of medical genetics. Part A 2024; (194(10)):e63777 doi:10.1002/ajmg.a.63777.

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    Recommendations of the Scientific Committee of the Italian Beckwith-Wiedemann Syndrome Association on the diagnosis, management and follow-up of the syndrome.

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    Adrenal Cortical Neoplasm with Uncertain Malignant Potential Arising in the Heterotopic Adrenal Cortex in the Liver of a Patient with Beckwith-Wiedemann Syndrome.

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This page provides educational information about Beckwith-Wiedemann Syndrome genetics and tumor risks. Always consult your pediatric geneticist or oncologist to discuss your child's specific subtype and clinical screening plan.

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