(Epi)genotype and Timing of Tongue Reduction Predict Safety and Long-Term Outcomes in Beckwith-Wiedemann Syndrome.

Background: Macroglossia is a cardinal feature of Beckwith-Wiedemann syndrome (BWS) with a clinical spectrum where the indication and timing for surgery remain to be validated. This study leverages a cohort of molecularly characterized patients with BWS to correlate epigenetic diagnosis with phenotype and treatment outcome.

Methods: Patients with BWS seen in consultation for macroglossia from 2009 to 2022 were reviewed for phenotype, molecular diagnosis, tongue reduction status, timing of surgery (early, less than 12 months), and perioperative complications.

Results: A total of 237 patients were included. Imprinting control region 2 loss of methylation was the most common epigenotype (61%). Paternal uniparental isodisomy for chromosome 11 included a larger proportion of patients undergoing tongue reduction (18%) than those not undergoing surgery (8%; P = 0.024) and was associated with need for repeated surgery (OR, 4.49; 95% CI, 1.06 to 18.98; P = 0.041). Complications including wound dehiscence, ventilator-associated pneumonia, and unplanned extubation were more common in patients undergoing early surgery (20%) than late surgery (4%; OR, 5.70; 95% CI, 1.14 to 28.55; P = 0.034).

Conclusions: This study presents one of the largest cohorts correlating molecular diagnosis with clinical course of macroglossia treatment in BWS. Macroglossia in patients with paternal uniparental isodisomy for chromosome 11 is associated with higher rates of reoperation. Relief of obstructive sleep apnea with early tongue reduction must be weighed against the risk of perioperative complications, most of which are nonsurgical. This study highlights how molecular diagnosis advances clinical care by risk stratifying clinical outcomes in a center providing integrated multidisciplinary care for the BWS population.

Clinical question/level of evidence: Risk, III.