Silver-Russell syndrome

Information about:

Silver-Russell syndrome (version Dec. 12th 2013)

(Russell-Silver syndrome, OMIM 180860)

Paternally expressed genes are labeled in blue and maternally expressed genes in red. The cytogenetic abnormalities associated with SRS are highlighted.

by David Monk and members of the

Silver Russell syndrome is a rare congenital developmental disorder that is clinically and genetically heterogeneous. Diagnosis is based on variable presentation of classical characteristics including pre- and postnatal growth failure, relative macrocephaly, frontal bossing in young age, triangular face, hemihypotrophy and fifth finger clinodactyly. Different diagnostic scoring systems have been proposed which incorporate the major features and utilize numerous minor anomalies for confirmation of diagnosis, such as feeding difficulties, excessive sweating, low-set/posteriorly rotated ears and café au lait patches.

However, a standardized scoring system does not exist. Furthermore many of the phenotypic features are non-specific, making clinical identification of SRS difficult. Therefore a major aim of this COST action is unifying clinical diagnosis, initially through the creation of a clinical utility gene card (Eggermann et al., 2011).

The first molecular abnormality observed in SRS was the identification of maternal uniparental disomy of chromosome 7 (mUPD7) accounting for 5-10% of individuals (Kotzot et al., 1995; Preece et al., 1997). This observation suggests the aberrant dosage of imprinted genes, however the precise gene(s) involved remain elusive. Chromosome 7 harbors several imprinting clusters; the GRB10 cluster at 7p12, a region duplicated in rare SRS-like individuals (Monk et al., 2000; Joyce et al., 1999), the PEG10 cluster at 7q21 and the interval surrounding MEST at 7q31, a region associated with segmental mUPD7 and paternally derived deletion (Hannula et al., 2001; Eggerman et al., 2012).

Recently, abnormalities of 11p15, a locus also harboring imprinted genes, have been described. This region contains two separate imprinting clusters that are mechanistically distinct. The telomeric cluster (ICR1) regulated by the H19 differentially methylated region (DMR) and the KvDMR1 (ICR2), which regulates the long non-coding RNA KCNQ1OT1, and CDKN1C genes. Of note, cytogenetic and epigenetic disturbances of ICR1 and ICR2 are associated with the over-growth disorder Beckwith-Wiedemann syndrome (BWS). Hypomethylation of the paternally methylated ICR1, which is associated with a concomitant decrease in IGF2 expression, is the most prevalent defect in SRS. This epimutation accounts for approximately 60% of individuals (Gicquel et al., 2005; Netchine et al., 2007), although it has been reported to occur less frequently in some populations (e.g. an incidence of ~31% in Japanese patients) (Fuke et al., 2013). Interestingly the level of H19 hypomethylation has been shown to correlate with the severity of the phenotype in some (Bliek et al., 2006; Bruce et al., 2009), but not all studies (Wakeling et al., 2010). Although no isolated epigenetic defects of ICR2 have been described in SRS, an involvement of one of the imprinted transcripts regulated by KCNQ1OT1 is implicated in the disease. Maternally derived loss-of-function mutations of the CDKN1C gene are classically associated with BWS (Lee et al., 1997). However, gain-of-function mutations within the proliferating cell nuclear antigen (PCNA)-binding domain of this gene have been reported in both IMAGe syndrome, characterized by intrauterine growth restriction (Arboleda et al., 2012), and familial SRS (Brioude et al., 2013).

The upper panel shows the reciprocal imprinting status of H19 and IGF2 on human chromosome 11p15. The region upstream of the H19 promoter is methylated solely on the paternal allele. The maternal allele is unmethylated and acts as a CTCF-dependent insulator. The middle panel represents the situation in a Silver Russell patient with ICR1 hypomethylation, which results in biallelic expression of the non-coding H19 transcript and a concomitant loss of IGF2 expression from the paternal allele. The lower panel shows the opposite situation that occurs in ~ 10% of Beckwith-Wiedemann syndrome patients. Hypermethylation of the ICR1 leads to activation of the normal repressed maternal allele of IGF2, leading to a double dose of this potent growth peptide.

Phenotypic assessment of patients has suggested that more classical features of SRS, like reduced birth weight and length, are more frequently associated with ICR1 hypomethylation, while patients with mUPD7 are more prone to have learning difficulties and mild speech problems (Hannula et al., 2001; Wakeling et al., 2010). Myoclonus-dystonia is also linked to mUPD7, the phenotype resulting from the absence of SGCE, a paternally transcribed gene within the 7q21-imprinted cluster (Sheridan et al., 2013). The presence of myoclonic jerks in SRS patients with mUPD7 might be under-reported since the symptoms are mild in childhood and typically manifest in adulthood.

A recent retrospective study has also suggested a difference in treatment response between individuals with ICR1 hypomethylation and mUPD7. Following growth hormone treatment, a recommended practice for these patients, individuals with mUPD7 tended to have better outcomes, with results comparable to those reported for non-syndromic SGA children (Binder et al., 2013). However final heights reached with growth hormone can be compromised in SRS patients because of rapid bone age maturation during adrenarche and puberty and some clinical trials are needed to address this issue and improve GH efficiency.

The majority of SRS patients with epigenetic errors have solitary ICR1 hypomethylation. However, similar to other imprinting disorders, a minority have multi-locus imprinting defects, which affect both maternally and paternally methylated DMRs, suggesting that the error is an imprint maintenance defect. Generally the additional epigenetic errors manifest as mild methylation defects restricted to a single or few additional DMRs, including IG-DMR, DIRAS3, NAP1L5, GRB10 and MEST (Azzi et al., 2009; Court et al., 2013; Fuke et al., 2013). In these rare cases, no additional clinical features were noted that would be attributable to methylation defects at other loci, suggesting an (epi)dominant effect of the ICR1 on the clinical phenotype.



 EMQN SRS Summary Report