New chromosome 11p15 epigenotypes identified in male monozygotic twins with Beckwith-Wiedemann syndrome

Abstract

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome demonstrating heterogeneous molecular alterations of two imprinted domains on chromosome 11p15. The most common molecular alterations include loss of methylation at the proximal imprinting center, IC2, paternal uniparental disomy (UPD) of chromosome 11p15 and hypermethylation at the distal imprinting center, IC1. An increased incidence of female monozygotic twins discordant for BWS has been reported. The molecular basis for eleven such female twin pairs has been demonstrated to be a loss of methylation at IC2, whereas only one male monozygotic twin pair has been reported with this molecular defect. We report here two new pairs of male monozygotic twins. One pair is discordant for BWS; the affected twin exhibits paternal UPD for chromosome 11p15 whereas the unaffected twin does not. The second male twin pair is concordant for BWS and both twins of the pair demonstrate hypermethylation at IC1. Thus, this report expands the known molecular etiologies for BWS twins. Interestingly, these findings demonstrate a new epigenotype-phenotype correlation in BWS twins. That is, while female monozygotic twins with BWS are likely to show loss of imprinting at IC2, male monozygotic twins with BWS reflect the molecular heterogeneity seen in BWS singletons. These data underscore the need for molecular testing in BWS twins, especially in view of the known differences among 11p15 epigenotypes with respect to tumor risk.

Beckwith–Wiedemann syndrome

“…This seems to be associated, at least in certain cases, with very high levels of paternal chromosome 11p15. 48 An increased frequency of female monozygotic twins discordant for BWS has been reported. 49 These females usually show loss of methylation at IC2.…”

“…In contrast, the less frequently observed male monozygotic twins show a broad spectrum of BWS-associated molecular alterations. 48 Subfertility/assisted reproductive technologies (ARTs). This seem to be associated with an increased risk of BWS cases with loss of methylation at IC2 (Figure 4).…”

“…Cardiomyopathy is rare and was recently reported in conjunction with high levels of UPD in two cases of BWS. 48 With respect to growth, there is no treatment indicated for macrosomia as final growth parameters are usually within normal limits; however, growth parameters should be followed regularly. If hemihyperplasia is present and involves the legs and/or trunk, screening for scoliosis should be included in routine physical examinations.…”

Non‐identical monozygotic twins, intermediate twin types, zygosity testing, and the non‐random nature of monozygotic twinning: A review

“…Recent publications are summarized in Tables II and III. The frequency of discordant BWS in MZ twin pairs is well known. The majority of these pairs are female, and the affected twins show loss of methylation at imprinting center 2 (IC2) of 11p15.5 [Smith et al, 2006]. However, concordance and discordance is also reported in male MZ pairs.…”

“…However, concordance and discordance is also reported in male MZ pairs. A discordant male pair showed paternal uniparental disomy for 11p15 in the affected twin [Smith et al, 2006]. Discordant trinucleotide expansion with discordant phenotype has been found in FRAX [Helderman-van den Enden et al, 1999].…”