Diagnosis and management of the phenotypic spectrum of twins with Beckwith-Wiedemann syndrome

Abstract

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with a heterogeneous phenotypic spectrum. There is an increased prevalence of monozygotic twinning in BWS. Given the epigenetic nature and phenotypic spectrum that defines BWS, twins are often discordant for clinical features, and clinicians are faced with the challenge of diagnosing and managing these twins. We present a cohort of multiple pregnancies in which one or more child from each pregnancy was diagnosed with BWS. We conducted a chart review of monochorionic and dichorionic gestations. Clinical scores for monochorionic twins demonstrated phenotypic discordance between the proband and twin. Based on linear regression analysis, a higher clinical score in the proband correlated with larger phenotypic discordance between twin siblings. Despite phenotypic discordance, however, we observed a consistent additive clinical score for a pregnancy (proband's plus twin's scores from a pregnancy). This idea of a finite degree of affectedness for a pregnancy implies a finite number of epigenetically affected cells. This further corroborates the idea that timing of monozygotic monochorionic twinning correlates with the disruption of establishment and/or maintenance of imprinting. The difference in clinical score between a proband and their twin may be due to diffused mosaicism, whereby there is an asymmetric distribution of affected cells among the multiple fetuses in a monozygotic monochorionic pregnancy, leading to a spectrum of variably affected phenotypes. Based on these findings, we recommend an algorithm for a conservative approach to clinically evaluate all children in a monozygotic multiple gestation affected by BWS.

Keywords: Beckwith-Wiedemann syndrome; mosaicism; multiple gestation; tumor screening; twin.

FIGURE 1

Linear regression showing clinical scores for 12 monochorionic twin pairs (there are only 10 distinct data points shown due to overlapping score pairs). The data points represent the BWS clinical score of the more affected twin of the gestation (proband) on the X axis, in relation to the difference in clinical score between the proband and twin sibling on the Y axis. The red data points represent the most phenotypically concordant twin pairs (difference ≤4). The best-fit line R² = .6432 with statistical significance (p = .0017)

FIGURE 2

Depiction of BWS average clinical scores for a cohort of patients with IC2 loss of methylation (LOM) as their molecular diagnosis. Average clinical score for a cohort of individuals is depicted above the respective bar in the graph. Abbreviations: MC, monochorionic; DC, dichorionic; mosaic LOM, mosaic loss of methylation at IC2; non-mosaic LOM, non-mosaic loss of methylation at IC2

FIGURE 3

Depiction of the proposed relationships between an imprinting event and the occurrence of twinning in embryogenesis, and a proposed mechanism of “diffused mosaicism” to explain phenotypic variability in the monochorionic twin cohort. (a) Non-mosaic LOM singleton; (b) mosaic LOM singleton; (c) dizygotic dichorionic discordant twins; (d) monozygotic dichorionic partially discordant twins (twin may be partially affected or unaffected); (e) monozygotic monochorionic concordant twins; (f) monozygotic monochorionic partially discordant twins; (g) monozygotic monochorionic discordant twins. A delay between the epigenetic event and twinning allows time for affected cell propagation, leading to two concordant embryos (e). When the twinning event occurs immediately following the epigenetic event, there is less time for affected cell division and dispersion, leading to two discordant embryos. For each category (a–g), the number of applicable pregnancies from our presented cohort is listed, followed by the average BWS clinical score for each child in the pregnancy (proband and twin, where applicable). The photographs depict representative patients from our cohort for each category

FIGURE 4

Proposed algorithm for clinical management of multiple gestations in which at least one child is affected with Beckwith-Wiedemann syndrome. Legend: † Clinical score excluding shared pregnancy factors (i.e., placental mesenchymal dysplasia, placentomegaly, polyhydramnios)‡ No data currently to support or refute the necessity of tumor screening in this instance