Relaxation of insulin-like growth factor 2 imprinting and discordant methylation at KvDMR1 in two first cousins affected by Beckwith-Wiedemann and Klippel-Trenaunay-Weber syndromes

Am J Hum Genet. 2000 Mar;66(3):841-7. doi: 10.1086/302811.


Beckwith-Wiedeman syndrome (BWS) and Klippel-Trenaunay-Weber syndrome (KTWS) are different human disorders characterized, among other features, by tissue overgrowth. Deregulation of one or more imprinted genes located at chromosome 11p15.5, of which insulin-like growth factor 2 (IGF2) is the most likely candidate, is believed to cause BWS, whereas the etiology of KTWS is completely obscure. We report a case of BWS and a case of KTWS in a single family. The probands, sons of two sisters, showed relaxation of the maternal IGF2 imprinting, although they inherited different 11p15.5 alleles from their mothers and did not show any chromosome rearrangement. The patient with BWS also displayed hypomethylation at KvDMR1, a maternally methylated CpG island within an intron of the KvLQT1 gene. The unaffected brother of the BWS proband shared the same maternal and paternal 11p15.5 haplotype with his brother, but the KvDMR1 locus was normally methylated. Methylation of the H19 gene was normal in both the BWS and KTWS probands. Linkage between the insulin-like growth factor 2 receptor (IGF2R) gene and the tissue overgrowth was also excluded. These results raise the possibility that a defective modifier or regulatory gene unlinked to 11p15.5 caused a spectrum of epigenetic alterations in the germ line or early development of both cousins, ranging from the relaxation of IGF2 imprinting in the KTWS proband to disruption of both the imprinted expression of IGF2 and the imprinted methylation of KvDMR1 in the BWS proband. Analysis of these data also indicates that loss of IGF2 imprinting is not necessarily linked to alteration of methylation at the KvDMR1 or H19 loci and supports the notion that IGF2 overexpression is involved in the etiology of the tissue hypertrophy observed in different overgrowth disorders, including KTWS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Alleles
  • Beckwith-Wiedemann Syndrome / genetics*
  • Beckwith-Wiedemann Syndrome / pathology
  • Chromosomes, Human, Pair 11 / genetics*
  • CpG Islands / genetics
  • DNA Methylation*
  • Female
  • Fibroblasts
  • Genes, Regulator / genetics
  • Genomic Imprinting / genetics*
  • Haplotypes / genetics
  • Humans
  • Insulin-Like Growth Factor II / genetics*
  • Introns / genetics
  • KCNQ Potassium Channels
  • KCNQ1 Potassium Channel
  • Klippel-Trenaunay-Weber Syndrome / genetics*
  • Klippel-Trenaunay-Weber Syndrome / pathology
  • Male
  • Mothers
  • Muscle Proteins / genetics
  • Pedigree
  • Polymorphism, Restriction Fragment Length
  • Potassium Channels / genetics
  • Potassium Channels, Voltage-Gated*
  • RNA, Long Noncoding
  • RNA, Untranslated*
  • Receptor, IGF Type 2 / genetics


  • 3' Untranslated Regions
  • H19 long non-coding RNA
  • KCNQ Potassium Channels
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • Muscle Proteins
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • RNA, Long Noncoding
  • RNA, Untranslated
  • Receptor, IGF Type 2
  • Insulin-Like Growth Factor II