Epigenetic anomalies in childhood growth disorders

Fetal growth is a complex process involving environmental, epigenetic and genetic factors. Fetal growth restriction is associated with morbidity among small for gestational age (SGA) neonates as well as in children and adults who were former SGA. Imprinted genes (whose expression is restricted to a single parental allele) have a critical role in controlling mammalian fetal growth. The human chromosome 11p15 encompasses two imprinted domains regulated by their own differentially methylated imprinted control region (ICR1 at the H19/IGF2 domain, and ICR2 at the KCNQ1/CDKN1C domain). Loss of imprinting at these two domains is implicated in two clinically opposite growth disorders. Indeed, our group has identified a loss of DNA methylation (LOM) at ICR1 in over 50% of patients with Russell-Silver syndrome (RSS) characterized by intrauterine and postnatal growth retardation with spared cranial growth, dysmorphic features, frequent body asymmetry and severe feeding difficulties. By contrast, gain of methylation at ICR1 is found in 10% of patients with Beckwith-Wiedemann syndrome (BWS), an overgrowth syndrome with an enhanced childhood tumor risk. We have now identified over 130 RSS patients with 11p15 LOM. This 11p15 epimutation is a frequent and specific cause of RSS as it has not been identified in non syndromic SGA patients. These new findings in the pathophysiology of RSS allow long-term follow-up studies to be performed based on molecular diagnosis. This will help to define appropriate clinical guidelines regarding growth, rapid bone age advance during puberty and feeding difficulties. Remarkably, we have also recently found that ∼10% of RSS patients and ∼25% of BWS patients showed multilocus LOM at imprinted regions other than ICR1 or ICR2 11p15, respectively. Several clinical studies demonstrated that assisted reproductive technology significantly increased the risk of human imprinting diseases including BWS and RSS, suggesting that the environment may favor imprinting disorders.