Abstract
BackgroundBeckwith-Wiedemann syndrome (BWS), a congenital overgrowth disorder with variable expressivity and a predisposition to tumorigenesis, results from disordered expression and/or function of imprinted genes at chromosome 11p15.5. There are no generally agreed clinical diagnostic criteria, with molecular studies commonly performed to confirm diagnosis. In particular, methylation status analysis at two 11p15.5 imprinting control centres (IC1 and IC2) detects up to 80% of BWS cases (though low-level mosaicism may not be detected). In order to evaluate the relationship between the clinical presentation of suspected BWS and IC1/2 methylation abnormalities we reviewed the results of >1,000 referrals for molecular diagnostic testing.ResultsOut of 1,091 referrals, 507 (46.5%) had a positive diagnostic test for BWS. The frequency of tumours was 3.4% in those with a molecular diagnosis of BWS. Previously reported genotype-phenotype associations with paternal uniparental disomy, IC1, and IC2 epimutation groups were confirmed and potential novel associations detected. Predictive values of previously described clinical diagnostic criteria were compared and, although there were differences in their sensitivity and specificity, receiver operating characteristic (ROC) analysis demonstrated that these were not optimal in predicting 11p15.5 methylation abnormalities. Using logistic regression, we identified clinical features with the best predictive value for a positive methylation abnormality. Furthermore, we developed a weighted scoring system (sensitivity 75.9%, and specificity 81.8%) to prioritise patients presenting with the most common features of BWS, and ROC analysis demonstrated superior performance (area under the curve 0.85, 95% CI 0.83 to 0.87) compared to previous criteria.ConclusionsWe suggest that this novel tool will facilitate selection of patients with suspected BWS for routine diagnostic testing and so improve the diagnosis of the disorder.
Highlights
Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth disorder with variable expressivity and a predisposition to tumorigenesis, results from disordered expression and/or function of imprinted genes at chromosome 11p15.5
Approximately 5 to 10% of children with BWS have a gain of methylation on the maternal IC1 allele, which is associated with biallelic expression of IGF2 and silencing of H19 expression
The most frequent indications for referral were: macroglossia (52.3%), anterior abdominal wall defects (44.8%; exomphalos in 22.8%, umbilical hernia in 21.5%, and diastasis recti in 5.4%), hemihypertrophy (41.4%), pre- or postnatal macrosomia (38.7%), ear creases/pits (36.4%), neonatal hypoglycaemia (29.8%), facial naevus flammeus (FNF, 24.1%), organomegaly (17.0%), polyhydramnios (10.1%), maxillary hypoplasia (9.6%), congenital heart defects (8.3%), and embryonal tumours (3.1%)
Summary
Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth disorder with variable expressivity and a predisposition to tumorigenesis, results from disordered expression and/or function of imprinted genes at chromosome 11p15.5. Beckwith-Wiedemann syndrome (BWS; MIM #130650), a congenital overgrowth disorder with a predisposition toward tumorigenesis, results from abnormal expression/ function of imprinted genes from the chromosome 11p15.5 imprinted gene cluster [1,2,3,4]. A further 50% of individuals with BWS have a loss of methylation at IC2 (KvDMR1); usually the paternal IC2 allele is unmethylated and the maternal allele is methylated, but in these cases both alleles are unmethylated [11,12] Such IC2 epimutations are associated with loss of function of the CDKN1C growth suppressor. Whilst the frequency of CDKN1C mutations is small (approximately 5%) in sporadic cases, mutations may be detected in about 50% of familial BWS cases [14,15]
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