Endocrine Abstracts

Introduction: Silver–Russell Syndrome (SRS) is a heterogeneous condition characterised by low birth weight, postnatal growth failure and clinical features including relative macrocephaly, limb or facial asymmetry and a triangular facies with broad forehead, pointed chin and downturned mouth. SRS been linked to a number of genetic abnormalities including maternal uniparental disomy (UPD), of chromosome 7 and hypomethylation of the IGF2-H19 imprinted region on chromosome 11p15.5. Approximately 50% of children with clinical SRS have no identified genetic cause.

Methods: We investigated 10 Caucasian patients with features of SRS using pyrosequencing to assess methylation at the IGF2-H19 locus and homozygosity mapping using Affymetrix 10K SNP arrays to assess maternal UPD across the genome. UPD was confirmed using microsatellite markers across the region.

Results: Two subjects, 1 male and 1 female, of the 10 showed maternal UPD at an imprinted locus on chromosome 14 with no evidence of microdeletions at this region. One of these also had reduced methylation at the 11p15.5 locus. The 2 patients, aged 10.85 and 10.93 years at the time of study, had height SDS −1.77 and −2.46 respectively. Birth weight SDS were −2.79 and −2.46 They had mild SRS features of relative macrocephaly, triangular facies and clinodactyly. Both children had normal peak GH responses on provocation of >25 miu/l.

Discussion: Maternal uniparental disomy of chromosome 14 has been previously described in SGA subjects with postnatal growth retardation, skeletal abnormalities and minor dysmorphic features. This is the first report to our knowledge of this genetic abnormality in SRS patients. We propose that uniparental disomy of chromosome 14 can result in a mild SRS phenotype.