Beckwith-Wiedemann Syndrome


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). Beckwith-Wiedemann syndrome is the most common overgrowth syndrome in infancy. 


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. [2]

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.

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.

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-2locus.
  • 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), theCDKN1C 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 inp57- null mice causes renomegaly.

    Laboratory Studies

    The following studies may be indicated in patients with suspected Beckwith-Wiedemann syndrome (BWS):

    • Proper documentation of hypoglycemia (blood glucose < 60 mg/dL) requires proper sample collection and processing. Guidelines for the monitoring and treatment of hypoglycemia have been established. [8, 9]

      • Ideally, blood samples for glucose assessment should be processed immediately after collection. Cells in the blood sample continue to metabolize glucose, even at cold temperatures, leading to falsely low glucose values and falsely high lactate values. Collecting the blood in a sodium fluoride-lined tube (gray top tube) inhibits glycolysis, reducing the likelihood of falsely low values.
      • Measurements made with portable glucometers are useful for screening but not for diagnosis of hypoglycemia. Portable glucometers are widely available and relatively inexpensive, which are their primary advantages in the outpatient management of diabetes mellitus. These devices, however, were not designed for accuracy because distinguishing between blood glucose values of 200 and 220 mg/dL, for example, is less important than making the device convenient and affordable. When compared with central laboratory assays, these glucometers display as high as 20% inaccuracy at the lower ranges. For diagnostic purposes (during fasting studies and in other hospital settings), blood glucose should be measured in the central hospital laboratory, preferably by the well-established glucose oxidase method. Portable glucometers remain useful for monitoring blood sugar on an outpatient basis, but persistent low values should prompt consultation with the physician.
      • At the time of hypoglycemia, obtain plasma ketones (acetoacetate and b-hydroxybutyrate), plasma free fatty acid, serum insulin, and serum IGF levels (IGF-1 and IGF-2 by radioimmunoassay; large molecular weight forms of IGF-2 can be detected by Western ligand blot).
      • If intravenous or intramuscular administration of 1 mg glucagon at the time of hypoglycemia results in a rise of blood glucose of at least 30 mg/dL above baseline, the test is consistent with inappropriately conserved glycogen stores as observed in hyperinsulinism or panhypopituitarism.

        Medical Care

        Patients with Beckwith-Wiedemann syndrome (BWS) may require frequent feedings or diazoxide to treat their hypoglycemia.

        • Octreotide or glucagon by subcutaneous infusion or injection is seldom necessary. [10]
        • The goal of therapy is maintenance of plasma glucose levels above 60 mg/dL at all times.
        • Infants and children must demonstrate the ability to maintain euglycemia during a fast of age-appropriate duration. The normal duration of fasting for an infant or child depends on body mass and the maturity of counterregulatory responses to hypoglycemia, which include gluconeogenesis, glycogenolysis, and ketogenesis.

          Surgical Care

          Embryonal tumors require appropriate oncologic treatment modalities, which often includes nephrectomy.

          Nephron-sparing partial nephrectomy is feasible if embryonal renal tumors are detected early, highlighting the need for frequent ultrasonographic screening.

          Macroglossia seldom requires resection to attain an independent airway. Macroglossia has been surgically reduced, with variable cosmetic outcomes

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