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

Beckwith-Wiedeman syndrome (BWS) and Klippel-Trenaunay-Weber syndrome (KTWS ) are different human disorders characterized, among other features, by tis sue overgrowth. Deregulation of one or more imprinted genes located at chro mosome 11p15.5, of which insulin-like growth factor 2 (IGF2) is the most li kely candidate, is believed to cause BWS, whereas the etiology of KTWS is c ompletely obscure. We report a case of BWS and a case of KTWS in a single f amily. The probands, sons of two sisters, showed relaxation of the maternal IGF2, imprinting, although they inherited different 11p15.5 alleles from t heir mothers and did not show any chromosome rearrangement. The patient wit h 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 hi s 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 overgrow th was also excluded. These results raise the possibility that a defective modifier or regulatory gene unlinked to 11p15.5 caused a spectrum of epigen etic alterations in the germ line or early development of both cousins, ran ging from the relaxation of IGF2 imprinting in the KTWS proband to disrupti on of both the imprinted expression of IGF2 and the imprinted methylation o f KvDMR1 in the BWS proband. Analysis of these data also indicates that los s 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 differen t overgrowth disorders, including KTWS.