Evolution of discrepancies in limb asymmetry in Beckwith-Wiedemann spectrum

Beckwith-Wiedemann spectrum is a genetic disorder characterized by lateralized overgrowth, often presenting as limb bulk discrepancy. While limb-length discrepancies are documented in Beckwith-Wiedemann spectrum, the natural history of limb bulk discrepancy and hand/foot asymmetry progression remains less studied. This research examines limb bulk discrepancy progression in children with Beckwith-Wiedemann spectrum and identifies factors influencing its severity.

A retrospective, single-institution study analyzed 142 children with molecularly confirmed Beckwith-Wiedemann spectrum (imprinting center 2 loss of methylation, imprinting center 1 gain of methylation, and paternal uniparental isodisomy at chromosome 11). Limb measurements (upper arm, forearm, thigh, calf, palm, finger, and foot) were recorded during clinic visits. Linear mixed-effects models assessed relationships between genotype, age, limb bulk discrepancy progression, body mass index, and sex.

The cohort included 90 imprinting center 2 loss of methylation, 41 paternal uniparental isodisomy at chromosome 11, and 11 imprinting center 1 gain of methylation patients. In the imprinting center 2 loss of methylation group, significant limb bulk discrepancy progression occurred in the upper arm (0.47 mm/year), calf (0.53 mm/year), and foot anterior-posterior dimension (0.40 mm/year; all p < 0.01). The paternal uniparental isodisomy at chromosome 11 genotype showed greater asymmetry in most regions compared to others (p < 0.01), except the middle finger. Asymmetry progression rates were similar across genotypes. Body mass index positively correlated with increased limb bulk discrepancy in the upper arm and calf.

Limb asymmetry in Beckwith-Wiedemann spectrum progresses slowly in specific regions, with genotype and body mass index influencing baseline severity. Patients with paternal uniparental isodisomy at chromosome 11 exhibit greater baseline limb bulk discrepancy, but progression rates are consistent across genotypes, highlighting the need for further research into lateralized overgrowth mechanisms and clinical implications.

3-Retrospective cohort study.