LAUSR

Background Silver-Russell syndrome (SRS) is a developmental disorder with extreme growth failure, characteristic facial features and underlying genetic heterogeneity. As the clinical heterogeneity of SRS makes diagnosis a challenging task, the worldwide incidence of SRS could vary from 1:30,000 to 1:100,000. Although various chromosomal, genetic and epigenetic mutation has been linked with SRS, but cause had been identified in half of the cases only. Material and Methods To have a better understanding of the SRS clinical presentation and mutation/epimutation responsible for SRS, a systematic review of the literature was carried out using appropriate keywords in various scientific databases (PROSPERO protocol registration CRD42021273211). Clinical features of SRS have been compiled and presented corresponding to the specific genetic subtype. An attempt has been made to understand recurrence risk, role of model organisms in understanding the molecular mechanisms of SRS pathology, treatment and management strategies of the affected patients through the analysis of selected literature. Results One hundred fifty six articles were selected to understand the clinical and molecular heterogeneity of SRS. Information about detailed clinical features were available for 228 patients only and it was observed that body asymmetry and relative macrocephaly were most prevalent in cases with methylation defects of the 11p15 region. In about 38% of cases, methylation defects in ICRs or genomic mutations at 11p15 region have been implicated. Maternal uniparental disomy of chromosome 7 (mUPD7) accounts for about 7% of SRS cases and rarely uniparental disomy of other autosomes (11, 14, 16 and 20 chromosomes) have been documented. Mutation in half of the cases is yet to be identified. Studies involving Mice as an experimental animal had been helpful in understanding the underlying molecular mechanism. As the clinical presentation of syndrome varies a lot, treatment needs to be individualized with multidisciplinary effort. Conclusion SRS is a clinically and genetically heterogeneous disorder with most of the cases being implicated with mutation in 11p15 region and disomy of chromosome 7. Recurrence risk varies according to the molecular subtype. Studies with Mice as a model organism has been useful in understanding the underlying molecular mechanism leading to characteristic clinical presentation of the syndrome. Management strategies often needs to be individualized due to varied clinical presentation.