Background: Genomic imprinting is an epigenetic mechanism referring to the monoallelic silencing of genes according to their parental origin. Human chromosome 11p15.5 encompasses two imprinted domains (ICR1 and ICR2) playing an important role in controlling fetal and postnatal growth. Genetic (uniparental disomy or gain/loss of function mutations) or epigenetic alterations at the 11p15.5 imprinted region (loss or gain of DNA methylation) are associated with two clinical disorders with opposite phenotypes: Silver-Russell syndrome (SRS, growth restriction, pubertal and metabolic disturbances) and Beckwith-Wiedemann syndrome (BWS, overgrowth with enhanced tumor risk during childhood).These epigenetic anomalies are thought to occur in a mosaic manner, postzygotically. Therefore, recent consensus about SRS and BWS highlighted the usefulness of testing alternative tissues in case of a normal molecular test in leucocytes. However, only few data have hitherto been reported in Human.
Methods: Allele-Specific Methylated Multiplex Real-Time Quantitative PCR was performed in fibroblasts for patients with a clinical diagnosis of SRS or a meeting the clinical criteria for BW spectrum (because of the presence of lateralized overgrowth) in which 11p15.5 molecular testing was normal in blood samples.
Results: Ten patients (three SRS and seven BWS) have been detected with normal methylation in leucocytes and abnormal methylation in fibroblasts. Three SRS patients met the clinical criteria for diagnosis of SRS with a score ≥ 4/6 in Netchine-Harbison clinical scoring system. All seven BWS patients had lateralized overgrowth (LO). Two patients presented with isolated LO. Embryonic tumours occured in two BWS patients (one bilateral Wilms tumor and one hepatoplastoma). One patient had macroglossia, another an ombilical hernia and one a nephromegaly. 11p15 loss of methylation has been detected in skin fibroblasts in three SRS patients, ICR1 11p15 gain of methylation in five BWS patients and ICR2 11p15 loss of methylation in two BWS patients. By contrast, DNA methylation analysis in leucocytes was normal in all patients.
Conclusion: 11p15 Methylation patterns may vary between different tissues. This can explain some cases of a negative molecular diagnosis when tested in blood samples for SRS and BWS. This is indeed in favor of a tissue mosaic distribution of these epigenetic anomalies and their postzygotic onset, and reinforces the usefulness of testing alternative tissues in case of clinical suspicion of BWS/SRS.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology