eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Beckwith-Wiedemann Syndrome

Author: Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis, and St Jude Children's Research Hospital; Field Surgeon (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Contributor Information and Disclosures

Updated: May 21, 2009

Introduction

Background

In 1964, Hans-Rudolf Wiedemann reported a familial form of omphalocele with macroglossia in Germany. In 1969, J. Bruce Beckwith of Loma Linda University, California, described a similar series of patients. Originally, Professor Wiedemann coined the term EMG syndrome to describe the combination of congenital exomphalos, macroglossia, and gigantism. Over time, this constellation was renamed Beckwith-Wiedemann syndrome (BWS).

Pathophysiology

Although the underlying causes of Beckwith-Wiedemann syndrome remain unclear, approximately 80% of patients demonstrate genotypic abnormalities of the distal region of chromosome arm 11p. The Beckwith-Wiedemann syndrome region of 11p was the first identified example of imprinting in mammals (ie, the process whereby the 2 alleles of a gene are expressed differentially). Authors have most often used the term imprinted to refer to the expressed allele. For example, the maternal allele of band 11p15.5 is normally expressed, or imprinted. Some authors, however, designate the silent allele as the imprinted gene.

When reviewing the literature, a reader must bear in mind this inconsistent and confusing nomenclature. Imprinting has been associated with structural modifications of DNA near the gene, such as methylation or lack of acetylation. Several 11p genes are imprinted, including p57 (a cation-independent cyclase), IGF-2 (the gene for insulinlike growth factor-2 [IGF-2]), the gene for insulin, and H19.

H19 is particularly interesting because this gene is transcribed but not translated. H19 messenger RNA (mRNA) appears critical for proper imprinting of the nearby insulin and IGF-2 genes because deletion of H19 or transposition from its usual position relative to IGF-2 disrupts normal imprinting. Evidence reveals that H19 mRNA binds IGF-2 mRNA binding protein, which may be one mechanism by which it affects IGF-2 production. 

The mode of inheritance in Beckwith-Wiedemann syndrome is complex. Reported patterns include autosomal dominance with variable expressivity, contiguous gene duplication at band 11p15.5, microdeletions, and aberrant genomic imprinting (resulting from a defective or absent copy of the maternally derived allele). Although not universal, the overgrowth associated with Beckwith-Wiedemann syndrome appears to be most often the result of increased IGF-2 action within prenatal and postnatal tissues.

Frequency

United States

US frequency is estimated at 1 in 15,000 live births.

International

Worldwide frequency is estimated at 1 in 13,700 live births in other developed countries. Incidence is also higher in infants produced with in vitro fertilization.

Mortality/Morbidity

Mental retardation is common. Strict maintenance of euglycemia reduces the risk of nervous tissue damage.

Race

No race predilection is observed.

Sex

No sex predilection is noted.

Age

Beckwith-Wiedemann syndrome is a congenital disorder. Wilms tumor is the most common cancer in children with Beckwith-Wiedemann syndrome, occurring in about 5-7% of all children with Beckwith-Wiedemann syndrome. Most children develop Wilms tumor before age 4 years; however, children with Beckwith-Wiedemann syndrome can develop Wilms tumor when they are as old as 7-8 years. By age 8 years, 95% of all Wilms tumor cases have been diagnosed.1

Clinical

History

  • Infants with Beckwith-Wiedemann syndrome (BWS) present large for gestational age and, typically, with neonatal onset of hypoglycemia.
  • The pregnancy is usually uncomplicated.

Physical

  • The cardinal features of Beckwith-Wiedemann syndrome include prenatal and postnatal overgrowth,2 macroglossia, and anterior abdominal wall defects (most commonly, exomphalos).
  • Variable findings include posterior helical indentations (pits of the external ear) and organ overgrowth, particularly hepatomegaly and nephromegaly.
  • Although mental retardation has been reported as a feature of Beckwith-Wiedemann syndrome, uncontrolled hypoglycemia during infancy, rather than congenital malformation of nervous tissue, may be a more significant etiologic factor.
  • Additional variable complications include organomegaly, hypoglycemia, hemihypertrophy, genitourinary abnormalities, and, in about 5-20% of children, embryonal tumors (most frequently Wilms tumor) and adrenal tumors such as adrenocortical neoplasias.

Causes

  • Beckwith-Wiedemann syndrome pathogenesis involves disrupted imprinting of one or more genes because the sex of the transmitting parent determines the pattern and risk of transmission in familial cases.
    • Maternal transmission is associated with dramatically greater penetrance.
    • Duplications of band 11p15.5 in patients with Beckwith-Wiedemann syndrome are always derived from the patient's father, whereas translocations and inversions are invariably derived from the patient's mother.
  • Approximately 15% of patients with Beckwith-Wiedemann syndrome cluster in families; the remainder are sporadic.
    • Most patients with sporadic Beckwith-Wiedemann syndrome lack apparent cytogenetic abnormalities; however, about 2% carry inversions, duplications, or translocations involving distal chromosome arm 11p.
    • At least 20% of sporadic cases manifest paternal uniparental disomy (UPD) for band 11p15.5, resulting from postzygotic mitotic recombination and mosaic paternal isodisomy.
    • Patients with Beckwith-Wiedemann syndrome and UPD, BWSIC1 mutations or 11p duplications lack exomphalos, whereas BWSIC2 mutations are commonly associated with exomphalos.
  • Three distinct breakpoint cluster regions (Beckwith-Wiedemann syndrome chromosome regions [BWSCRs]) encompass the maternally derived rearrangements associated with Beckwith-Wiedemann syndrome.
    • The most common breakpoint is BWSCR1, which interrupts the KvLQT1 (KCNQ1) gene and maps at least 200 kilobases (kb) proximal to the IGF-2 gene.
    • KvLQT1 encodes multiple transcripts, including a potassium channel (unrelated to BWS), which, when mutated, results in cardiac conduction disorders (Jervell and Lange-Nielsen syndrome and long QT syndrome).
    • Rare breakpoint cluster regions, BWSCR2 and BWSCR3, map approximately 5 megabases (Mb) and 7 Mb centromeric to BWSCR1.
  • Most patients with Beckwith-Wiedemann syndrome demonstrate biallelic expression of IGF-2 in various tissues. Some patients with Beckwith-Wiedemann syndrome demonstrate elevated serum levels of IGF-2, which may reflect leakage into the vasculature from tissues with elevated production. Because 20% of patients with Beckwith-Wiedemann syndrome have no identified genotypic disorder, one should not conclude that somatic overgrowth in patients with Beckwith-Wiedemann syndrome must result from tissue IGF-2 overexpression. Several murine models have provided tantalizing glimpses into potential pathophysiologies for the diverse spectrum of Beckwith-Wiedemann syndrome phenotypes.
  • IGF-2 overexpression in transgenic mice induces dose-dependent organomegaly, overgrowth, and macroglossia.
    • IGF-2–receptor null mice demonstrate elevated serum IGF-2 levels and fetal overgrowth (birthweight 135% of wild-type).
    • H19 null mice manifest loss of imprinted transcriptional regulation at the IGF-2 locus.
    • The crossing of H19 null with IGF-2–receptor null mice results in loss of imprinting at the IGF-2 locus and reduced clearance of IGF-2. These double null mice (H19 –/–/IGF-2R –/–) display higher serum IGF-2 levels than the IGF-2 transgenic mice and exhibit exomphalos and overgrowth.
    • In a model of patients with Beckwith-Wiedemann syndrome and germline mutations of CDKN1C (the gene for cyclin-dependent kinase inhibitor 1C), the CDKN1C knockout mouse manifests anterior abdominal wall defects, adrenal cortical cytomegaly, and renal medullary dysplasia but lacks overgrowth and other features of Beckwith-Wiedemann syndrome.
    • Prenatal exomphalos without overgrowth develops in p57 (Kip2)—null mice, and death ensues shortly after birth. Defective closure of the secondary palate in p57 null mice allows aspiration of milk and swallowing of air, which inflates and then stretches the stomach and intestines. Renal medullary dysplasia in p57- null mice causes renomegaly.

More on Beckwith-Wiedemann Syndrome

Overview: Beckwith-Wiedemann Syndrome
Differential Diagnoses & Workup: Beckwith-Wiedemann Syndrome
Treatment & Medication: Beckwith-Wiedemann Syndrome
Follow-up: Beckwith-Wiedemann Syndrome
Multimedia: Beckwith-Wiedemann Syndrome
References
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Further Reading

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Keywords

Beckwith-Wiedemann syndrome, BWS, exomphalos, macroglossia, congenital exomphalos, congenital macroglossia, gigantism syndrome, EMG syndrome, Wilms tumor, omphalocele with macroglossia, hepatoblastoma, organomegaly, hypoglycemia, anterior abdominal wall defects, helical indentations, organ overgrowth, nephromegaly, hemihypertrophy, genitourinary abnormalities, embryonal tumors, adrenocortical neoplasias, treatment, diagnosis

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Contributor Information and Disclosures

Author

Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis, and St Jude Children's Research Hospital; Field Surgeon (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society
Disclosure: Nutropin Speakers Bureau Honoraria Speaking and teaching; Genotropin Speakers Bureau Honoraria Speaking and teaching; Eli Lilly & Co. Grant/research funds Independent contractor; MacroGenics, Inc. Grant/research funds Independent contractor; Ipsen, S.A. (formerly Tercica, Inc.) Grant/research funds Independent contractor

Medical Editor

Phyllis W Speiser, MD, Chief of Pediatric Endocrinology, Schneider Children's Hospital; Professor of Pediatrics, New York University School of Medicine
Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Barry B Bercu, MD, Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital
Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Federation for Clinical Research, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Lawson-Wilkins Pediatric Endocrine Society, Pituitary Society, Society for Pediatric Research, Society for the Study of Reproduction, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Genentech, Inc. Honoraria Speaking and teaching; Pfizer, Inc. Honoraria Consulting

 
 
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