First report on concordant monozygotic twins with Silver–Russell syndrome and ICR1 hypomethylation

Twin pairs with the imprinting disorder Silver–Russell syndrome (SRS) have rarely been reported. All six monozygotic (MZ) twin pairs described so far were clinically discordant. In two of the four SRS twin pairs with molecularly proven 11p15.5 epimutation, the healthy twin also showed the molecular alteration in blood cells, but not in the other tested tissues. The clinical discordance is a well-known but poorly understood observation because MZ twins derive from the same zygote. For the second 11p15.5-associated imprinting disorder, Beckwith-Wiedemann syndrome, a larger number of twins has been described, here the majority of pairs are MZ but clinically discordant as well. Interestingly, there is a considerable preponderance of females among the MZ twins with BWS, and a functional link between altered imprinting and X chromosome inactivation has been suggested. We now describe two further MZ SRS twins with H19/IGF2:IG-DMR hypomethylation, including the first clinically concordant pair. By summarizing the existing data, an excess of females in MZ twins with SRS is observed, thus confirming the hypothesis that X-chromosome inactivation might trigger the inaccurate methylation of imprinted loci at least in female twin conceptions. The occurrence of a MZ concordant SRS twin pair is exceptional. The detailed molecular characterization of both siblings of a twin pair enables a reliable diagnosis, furthermore it allows insights in the etiology of twinning in association with (aberrant) imprinting marking.