Last Updated: October 31, 2022
Introduction to Beckwith-Wiedemann Syndrome
Beckwith-Wiedemann syndrome (BWS) is the most well characterized disorder affecting growth that results from defects in the process of genomic imprinting. The overall frequency of BWS is 1 in 13,700. The disorder is found with equal distribution between males and females and has been identified in numerous ethnic populations. Approximately 85% of BWS cases are sporadic while the other 15% demonstrate autosomal dominant inheritance.
Molecular Biology of Beckwith-Wiedemann Syndrome
Beckwith-Wiedemann syndrome (BWS) is caused by alterations (both genetic and epigenetic) in a 1 Mb region of chromosome 11 (11p15.5) that consists of two imprinting domains encompassing at least 15 genes. These two imprinted domains are identified as differentially methylated regions 1 (DMR1) and DMR2. DMR are also known as imprinting control regions (ICR). Alterations in two genes (one in DMR1 and one in DMR2) are considered key events in the genesis of BWS.
There are five identified genetic and epigenetic alterations that have been shown to be causative for BWS. These alterations are loss of methylation (LOM), gain of methylation (GOM), paternal uniparental disomy (paternal UPD), mutations, and chromosomal rearrangements. The most prominent genetic alterations found in BWS patients are LOM (~50% of cases) and paternal UPD (~20% of cases). The critical genes in DMR1 are the IGF2 and H19 genes and those in the DMR2 are the CDKN1C and KCNQ10T1 genes.
Loss of methylation
The IGF2 gene encodes the growth factor, insulin-like growth factor 2. The H19 gene encodes long non-coding RNA (lncRNA) that has been suspected to act as a tumor suppressor. The CDKN1C gene encodes the cell cycle regulator p57KIP2. The KCNQ1OT1 gene resides within intron 10 of the KCNQ1 (encodes a subunit of a voltage-gated potassium channel, was previously called KvLQT1) gene. The KCNQ10T1 gene encodes a lncRNA and it is transcribed in the antisense direction relative to KCNQ1.
The IGF2 gene is normally only expressed from the paternal chromosome and this parental-specific expression pattern is controlled by an imprinting control element that lies close to the maternally imprinted neighboring gene identified as H19. The H19 promoter, as well as the imprinting center (DMR1) located several kb upstream, are differentially methylated. The paternal allele is methylated whereas, the maternal allele is not. Expression of IGF2 and H19 is coordinated by DMR1 such that on the maternal chromosome only H19 is expressed and on the paternal chromosome only IGF2 is expressed. The CDKN1C gene resides approximately 700 kb from both IGF2 and H19 and it too is maternally expressed.
The CDKN1C gene is located in domain 2 which reside centromeric to domain 1 on chromosome 11. There are several other imprinted genes in the region of CDKN1C but mutations in CDKN1C are most associated with BWS relative to any of the other genes in domain 2. Since the CDKN1C gene encodes a cyclin-dependent kinase inhibitor it is involved in negative regulation of cell proliferation. It functions as both a tumor suppressor and as a potential negative regulator of fetal growth. Expression of the genes in domain 2 are regulated by the imprinting center called DMR2. Normally the maternal allele of DMR2 is methylated. Loss of maternal methylation of DMR2 is seen in 50%-60% of patients with sporadic BWS.
Other potentially important genes in domain 2 of chromosome 11 that are implicated in BWS and/or growth regulation are KCNQ1 (encodes a subunit of a voltage-gated potassium channel, was previously called KvLQT1), KCNQ1OT1 [this gene, present in intron 10 of the KCNQ1 gene, encodes a long non-coding RNA (lncRNA) expressed in the antisense direction relative to KCNQ1], PHLDA2 (plekstrin homology-like domain, family A, member 2), and SLC22A18 [solute carrier family 22 (organic cation transporter), member 18].
Clinical Features of Beckwith-Wiedemann Syndrome
The cardinal features of BWS are exomphalos (an umbilical hernia at birth in which some abdominal organs push into the umbilical cord), macroglossia (an enlarged tongue), and gigantism (specifically embryonic and placental overgrowth). These three cardinal symptoms led to an original designation of this disorder as EMG syndrome. In addition, individuals with BWS have a predisposition to childhood cancers. These cancers include Wilms tumor (a kidney cancer), adrenocortical cancer, hepatoblastoma, and rhabdomyosarcoma.