Beckwith-Wiedemann Syndrome Clinical Presentation: History, Physical, Causes

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Sections Beckwith-Wiedemann Syndrome
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Presentation

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,^[4]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. ^{[5, 6]}
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). ^[7]
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.

Differential Diagnoses

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Media Gallery

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

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Author

Sunil Kumar Sinha, MD

Sunil Kumar Sinha, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

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 Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Pediatric Endocrine Society, Society for Pediatric Research, Southern Society for Pediatric Research, Society for the Study of Reproduction, American Federation for Clinical Research, Pituitary Society

Disclosure: Nothing to disclose.

Chief Editor

Robert P Hoffman, MD Professor and Program Director, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Division of Pediatric, Endocrinology, Diabetes, and Metabolism, Nationwide Children's Hospital

Robert P Hoffman, MD is a member of the following medical societies: American College of Pediatricians, American Diabetes Association, American Pediatric Society, Christian Medical and Dental Associations, Endocrine Society, Midwest Society for Pediatric Research, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Phyllis W Speiser, MD Chief, Division of Pediatric Endocrinology, Steven and Alexandra Cohen Children's Medical Center of New York; Professor of Pediatrics, Hofstra-North Shore LIJ School of Medicine at Hofstra University

Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

Robert J Ferry Jr, MD Le Bonheur Chair of Excellence in Endocrinology, Professor and Chief, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center

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, Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Eli Lilly & Co Grant/research funds Investigator; MacroGenics, Inc Grant/research funds Investigator; Ipsen, SA (formerly Tercica, Inc) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Grant/research funds Investigator; Bristol-Myers-Squibb Grant/research funds Other; Amylin Other; Pfizer Grant/research funds Other; Takeda Grant/research funds Other

Sections Beckwith-Wiedemann Syndrome
Overview
Presentation
- History
- Physical
- Causes
- Show All
DDx
Workup
Treatment
Medication
Follow-up
References

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