Beckwith-Wiedemann Syndrome Clinical Presentation

  • Author: Robert J Ferry Jr, MD; Chief Editor: Stephen Kemp, MD, PhD   more...
 
Updated: Apr 15, 2010
 

History

Infants with Beckwith-Wiedemann syndrome (BWS) present large for gestational age and, typically, with neonatal onset of hypoglycemia.

The pregnancy is usually uncomplicated.

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Physical

The cardinal features of Beckwith-Wiedemann syndrome include prenatal and postnatal overgrowth,[3] 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.

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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.
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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 Hospital; Professor, Department of Pediatrics, University of Tennessee Health Science Center at Memphis; St. Jude Children's Research Hospital, Memphis, TN; Brigade Surgeon, 36th Sustainment Brigade, U.S. Army; Adjunct Professor, Pediatric Surgery Department, King Saud University, Riyadh, Saudi Arabia

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; NovoNordisk SA Grant/research funds Independent contractor; Diamyd Independent contractor

Specialty Editor Board

Phyllis W Speiser, MD  Chief, Division of Pediatric Endocrinology, The Children's Hospital, North Shore LIJ Health System; 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.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

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.

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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Gross nephrectomy specimen shows a Wilms tumor pushing the normal renal parenchyma to the side.
 
 
 
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