Investigation of (epi)genotype causes and follow-up manifestations in the patients with classical and atypical phenotype of Beckwith-Wiedemann spectrum

Beckwith-Wiedemann syndrome (BWS) is a genomic imprinting disorder, characterized by macroglossia, abdominal wall defects, lateralized overgrowth, and predisposition to embryonal tumors. It is caused by the defect of imprinted genes on chromosome 11p15.5, regulated by imprinting control (IC) domains, IC1, and IC2. Rarely, CDKN1C and chromosomal changes can be detected. The aim of this study is to retrospectively evaluate 55 patients with BWS using the new diagnostic criteria developed by the BWS consensus, and to investigate (epi)genetic changes and follow-up findings in classic and atypical phenotypes. Loss of methylation in IC2 region (IC2-LoM), 11p15.5 paternal uniparental disomy (pUPD11), and methylation gain in IC1 region (IC1-GoM) are detected in 31, eight, and five patients, respectively. Eleven patients have had no molecular defects. Thirty-five patients are classified as classical and 20 as atypical phenotype. Patients with classical phenotype are more frequent in the IC2-LoM (25/31), while patients with atypical phenotype are common in the pUPD11 group (5/8). Malignant tumors have developed in six patients (10.9%); three of these patients have IC1-GoM, two pUPD11, one IC2-LoM genotype, and four an atypical phenotype. We observed that the face was round in the infantile period and elongated as the child grew-up, developing prognathism and becoming asymmetrical if hemi-macroglossia was present in the classical phenotype. These findings were mild in the atypical phenotype. These results support the importance of using the new diagnostic criteria to facilitate the diagnosis of patients with atypical phenotype who have higher tumors risk. This study also provides important information about facial gestalt.