Beckwith-Wiedemann Syndrome Revisited.

Abstract

Beckwith–Wiedemann syndrome (BWS) is an overgrowth syndrome due to dysregulation of the imprinted region on chromosome 11p15. Like many syndromes, the clinical presentation is highly variable often including macrosomia, macroglossia, hemihyperplasia, and abdominal wall defects as well as visceromegaly. It can be associated with a number of minor features, such as neonatal hypoglycemia, ear anomalies, and nevus flammus. During childhood, there is an increased risk of developing tumors of embryological origin. It has been hypothesized that the variable presentation can be genetically explained. Accordingly, several genotype–phenotype correlation studies have been conducted for BWS and 11p15 methylation defects and molecular subgroups are now emerging. Most cases of BWS are sporadic, although a familial form exists. CDKN1 (cyclin-dependent kinase inhibitor 1C) is implicated in 8% of BWS patients, explaining 40% of familial and 5% of sporadic cases in the literature. In this issue, Brioude et al. (Hum Mutat 36:894–902, 2015) have ascertained and clinically characterized a large collection of 38 families, in which they identified 32 original and five recurrent CDKN1 mutations. Possible gonadal germline mosaicism was also described in one family. The authors propose an in vitro test to evaluate the functional implications of these alterations at the protein level, as CDKN1C is known to be involved in the regulation of cell proliferation. Importantly, in this cohort, nonsense and frameshift mutations were responsible for a more severe phenotype, with all tumors occurring in patients with frameshift mutations. Overall, the spectrum of tumors observed in patients with CDKN1C variants appears to be different and the risk appears to be lower as compared with other types of BWS. Although the authors are cautious about the low rate of tumors and about making possible changes in the screening program, their study should be a reference for further investigations. The authors conclude their findings in CDKN1C-positive patients by proposing guidelines for CDKN1C testing when 11p15 methylation analysis is normal for sporadic cases with umbilical hernia or exomphalos without hemihyperplasia, and in familial cases. In the future, the genotype–phenotype correlation will certainly allow personalized screening programs for children affected by BWS. Adapting the tumor surveillance program to the BWS molecular subgroup will minimize the number of examinations and tests performed and the psychological burden on patients and their families.