Excerpt from Beckwith-Wiedemann Syndrome

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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, Calif, 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 BWS remain unclear, approximately 80% of patients demonstrate genotypic abnormalities of the distal region of chromosome arm 11p. The BWS 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. Recent 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 BWS 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 BWS 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

BWS is a congenital disorder. Wilms tumor is the most common cancer in children with BWS, occurring in about 5-7% of all children with BWS. Most children develop Wilms tumor before age 4 years; however, children with BWS can develop Wilms tumor when they are as old as 7 or 8 years. By age 8 years, 95% of all Wilms tumor cases have been diagnosed (DeBaun, 1998).

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