Approach to the Patient With Suspected Silver-Russell Syndrome

Abstract

Silver-Russell syndrome (SRS) is a clinical diagnosis requiring the fulfillment of ≥ 4/6 Netchine-Harbison Clinical Scoring System (NH-CSS) criteria. A score of ≥ 4/6 NH-CSS (or ≥ 3/6 with strong clinical suspicion) warrants (epi)genetic confirmation, identifiable in ∼60% patients. The approach to the investigation and diagnosis of SRS is detailed in the only international consensus guidance, published in 2016. In the intervening years, the clinical, biochemical, and (epi)genetic characteristics of SRS have rapidly expanded, largely attributable to advancing molecular genetic techniques and a greater awareness of related disorders. The most common etiologies of SRS remain loss of methylation of chromosome 11p15 (11p15LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). Rarer causes of SRS include monogenic pathogenic variants in imprinted (CDKN1C and IGF2) and non-imprinted (PLAG1 and HMGA2) genes. Although the age-specific NH-CSS can identify more common molecular causes of SRS, its use in identifying monogenic causes is unclear. Preliminary data suggest that NH-CSS is poor at identifying many of these cases. Additionally, there has been increased recognition of conditions with phenotypes overlapping with SRS that may fulfill NH-CSS criteria but have distinct genetic etiologies and disease trajectories. This group of conditions is frequently overlooked and under-investigated, leading to no or delayed diagnosis. Like SRS, these conditions are multisystemic disorders requiring multidisciplinary care and tailored management strategies. Early identification is crucial to improve outcomes and reduce the major burden of the diagnostic odyssey for patients and families. This article aims to enable clinicians to identify key features of rarer causes of SRS and conditions with overlapping phenotypes, show a logical approach to the molecular investigation, and highlight the differences in clinical management strategies.

Keywords: NH-CSS; Silver-Russell syndrome; diagnosis; genetic.

Figure 1.

Proposed mechanisms in Silver-Russell syndrome (SRS) and Temple syndrome leading to growth restriction. A, Representation of the 11p15 region, showing the paternal and maternal telomeric H19/IGF2 IG-DMR (ICR1) and centromeric KCNQ1OT1 TSS-DMR (ICR2) imprinting control regions associated with SRS. A differentially paternally methylated region between the IGF2 and H19 genes regulates expression. Aberrant expression of genes (upstream or within the imprinting control region) controlling the IGF2 gene (paternally expressed fetal growth factor) and H19 (maternally expressed) expression leads to growth restriction. B, Representation of the 14q32 region implicated in Temple syndrome (TS14). TS14 can be caused by 3 mechanisms: maternal UPD leading to expression of only maternally expressed genes from both chromosomes, paternal loss of methylation of MEG3/DLK1 IG-DMR resulting in a maternal chromosome-like expression pattern, or deletion in the paternal chromosome resulting in absence of paternally expressed genes. Aberrant expression of these genes is associated with IGF2 downregulation, leading to growth restriction. Gray boxes indicate expressed genes; open boxes, silenced genes; black box, activating mutation (CDKN1C); X, pathogenic loss-of-function mutations (HMGA2, IGF2, PLAG1).

Figure 2.

Flow chart for the investigation and diagnosis of Silver-Russell syndrome (SRS) and conditions with phenotypes overlapping with SRS.