(Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome

Abstract

Beckwith-Wiedemann syndrome (BWS) is characterized by cancer predisposition, overgrowth and highly variable association of macroglossia, abdominal wall defects, nephrourological anomalies, nevus flammeus, ear malformations, hypoglycemia, hemihyperplasia, and organomegaly. BWS molecular defects, causing alteration of expression or activity of the genes regulated by two imprinting centres (IC) in the 11p15 chromosomal region, are also heterogeneous. In this paper we define (epi)genotype-phenotype correlations in molecularly confirmed BWS patients. The characteristics of 318 BWS patients with proven molecular defect were compared among the main four molecular subclasses: IC2 loss of methylation (IC2-LoM, n=190), IC1 gain of methylation (IC1-GoM, n=31), chromosome 11p15 paternal uniparental disomy (UPD, n=87), and cyclin-dependent kinase inhibitor 1C gene (CDKN1C) variants (n=10). A characteristic growth pattern was found in each group; neonatal macrosomia was almost constant in IC1-GoM, postnatal overgrowth in IC2-LoM, and hemihyperplasia more common in UPD (P<0.001). Exomphalos was more common in IC2/CDKN1C patients (P<0.001). Renal defects were typical of UPD/IC1 patients, uretheral malformations of IC1-GoM cases (P<0.001). Ear anomalies and nevus flammeus were associated with IC2/CDKN1C genotype (P<0.001). Macroglossia was less common among UPD patients (P<0.001). Wilms' tumor was associated with IC1-GoM or UPD and never observed in IC2-LoM patients (P<0.001). Hepatoblastoma occurred only in UPD cases. Cancer risk was lower in IC2/CDKN1C, intermediate in UPD, and very high in IC1 cases (P=0.009). In conclusion, (epi)genotype-phenotype correlations define four different phenotypic BWS profiles with some degree of clinical overlap. These observations impact clinical care allowing to move toward (epi) genotype-based follow-up and cancer screening.

Figure 1

Differences in the prevalence of the features in the molecular subtypes of the syndrome: (a) neonatal overgrowth, (b) postnatal overgrowth, (c) hemihyperplasia, (d) normal growth, (e) omphalocele, (f) umbilical hernia, (g) diastasis recti, (h) no abdominal wall defect, (i) macroglossia, (j) ear malformations, (k) naevus flammeus, (l) cleft palate, (m) organ enlargment, (n) renal anomalies, (o) ureteral anomalies, (p) malignant neoplasms, (q) benign neoplasms, (r) preterm birth, (s) polyhydramnios, (t) hypoglycemia. P-values in the corner of panels refer to the comparison among the four groups, P-values above columns to the comparison of each molecular subtype with the other three (non-significant values not shown).

Figure 2

Enrichment of the abdominal wall defects in the molecular groups.

Figure 3

Kaplan–Meier plot of the tumor-free interval (malignant neoplasms only) in the three main molecular subtypes of Beckwith–Wiedemann syndrome (BWS). IC2-LoM: imprinting center 2 loss of methylation, UPD: paternal uniparental disomy; IC1-GoM: imprinting center 1 gain of methylation.