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.

Preclinical and Clinical Epigenetic-Based Reconsideration of Beckwith-Wiedemann Syndrome

“…In 10 MZ, 9 were females, and all 3 cases of DZ were females (Bliek et al, 2009a). More recently, in 2019, the high incidence of monozygotic female in a cohort of 26 BWS twins was confirmed (Cohen et al, 2019). The significant female preponderance of the MZ discordant for BWS could be associated with a variety of sex-related factors.…”

“…The mosaicism is leading to a discordance between MZ in BWS, and it is linked to an epigenetic event triggered by the twinning process. Cells involved in this event spread among embryos in a multiple pregnancy creating a mosaic distribution being responsible for the variable phenotypic spectrum observed in BWS cases ( Cohen et al, 2019 ). The timing of epigenetic aberrations influences the twinning, the degree of severity of BWS, and the degree of mosaicism.…”

“…The timing of epigenetic aberrations influences the twinning, the degree of severity of BWS, and the degree of mosaicism. The theory of “diffuse mosaicism” proposed by Cohen et al (2019) outlines the time points when the epigenetic event occurs in relation to twinning and the determination of chorionicity. In singleton gestations, the epigenetic aberration has been reported to occur first in non-mosaic patients during embryogenesis and subsequently in mosaic patients.…”

“…In dichorionic gestations, the zygosity determines the timing of the event. It occurs earlier in the dizygotic dichorionic pregnancies than in the monozygotic dichorionic pregnancies ( Cohen et al, 2019 ). Previous research has shown that an epigenetic event before twinning leads to the formation of two different clonal cell populations ( Bell and Spector, 2011 ).…”

“…This failure occurs in the eight-cell blastocyst stage preceding the moment when MZ (monochorionic, diamniotic) twinning is established. However, not all methylation defects involve twinning, and most BWS patients are singletons ( Cohen et al, 2019 ). An explanation of these assumptions is related to the theory of endangered twins in which twinning occurs in all cases, but the second fetus is reabsorbed in early pregnancy ( Landy and Keith, 1998 ).…”