Genetic and epigenetic findings in Silver-Russell syndrome

Silver-Russell syndrome (SRS) is a genetically and clinically heterogeneous disease which is mainly characterized by pre- and postnatal growth restriction. The typical SRS phenotype furthermore includes a relative macrocephaly, a triangular shaped face, body asymmetry, clinodactyly of the fifth finger and other less constant features. In about ~50% of patients (epi)genetic alterations involving chromosomes 7 and 11 can be detected. The major finding (~44%) is a hypomethylation of the imprinting control region 1 (ICR1) in 11p15.5 affecting the expression of H19 and IGF2. 4-10% of the patients carry a maternal UPD of chromosome 7 (UPD(7)mat). In a few cases chromosomal rearrangements have been reported. The diagnostic workup should therefore include 11p15 testing, UPD(7)mat analysis and molecular karyotyping. The recurrence risk is generally low in SRS but it can strongly increase in case of familial epimutations or chromosomal rearrangements. Interestingly, in ~7% of 11p15 hypomethylation carriers, hypomethylation of additional imprinted loci can be detected. Clinically, patients with hypomethylation at multiple loci do not differ from those with isolated ICR1 hypomethylation whereas the UPD(7)mat patients generally show a milder phenotype. Nevertheless, an unambiguous (epi)genotype-phenotype correlation can not be delineated. Furthermore, the pathophysiological mechanisms resulting in the SRS phenotype still remain unknown despite the recent progress in deciphering molecular defects in the disease.