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 EUCID.net
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.
The majority of SRS patients are diagnosed during their early childhood years, as some of the characteristic features become less noticeable with time making diagnosis difficult in adults. Therefore there is a lack of information with regards to the long-term consequence of the disease in adults that could have important implications for endocrine, metabolic and reproductive outcomes. The mechanisms leading to these ICR1 hypomethylation are important to decipher, allowing for informed genetic counseling. Approximately 30% of SRS patients are idiopathic with no molecular anomaly yet identified. Consensual clinical diagnosis and clinical guidelines will be important to establish, as well as a quality control for molecular diagnosis.
Kotzot D, Schmitt S, Bernasconi F, Robinson WP, Lurie IW, Ilyina H, Méhes K, Hamel BC, Otten BJ, Hergersberg M, et al. Uniparental disomy 7 in Silver-Russell syndrome and primordial growth retardation. Hum Mol Genet. 1995; 4: 583-7.
Preece MA, Price SM, Davies V, Clough L, Stanier P, Trembath RC, Moore GE. Maternal uniparental disomy 7 in Silver-Russell syndrome. J Med Genet. 1997; 34: 6-9.
Joyce CA, Sharp A, Walker JM, Bullman H, Temple IK. Duplication of 7p12.1-p13, including GRB10 and IGFBP1, in a mother and daughter with features of Silver-Russell syndrome.Hum Genet. 1999; 105: 273-80.
Hannula K, Lipsanen-Nyman M, Kontiokari T, Kere J. A narrow segment of maternal uniparental disomy of chromosome 7q31-qter in Silver-Russell syndrome delimits a candidate gene region.Am J Hum Genet. 2001; 68: 247-53.
Eggermann T, Spengler S, Begemann M, Binder G, Buiting K, Albrecht B, Spranger S. Deletion of the paternal allele of the imprinted MEST/PEG1 region in a patient with Silver-Russell syndrome features. Clin Genet. 2012; 81: 298-300.
Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, Danton F, Thibaud N, Le Merrer M, Burglen L, Bertrand AM, Netchine I, Le Bouc Y. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet. 2005; 37: 1003-7.
Netchine I, Rossignol S, Dufourg MN, Azzi S, Rousseau A, Perin L, Houang M, Steunou V, Esteva B, Thibaud N, Demay MC, Danton F, Petriczko E, Bertrand AM, Heinrichs C, Carel JC, Loeuille GA, Pinto G, Jacquemont ML, Gicquel C, Cabrol S, Le Bouc Y. 11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations. J Clin Endocrinol Metab. 2007; 92: 3148-54.
Fuke T, Mizuno S, Nagai T, Hasegawa T, Horikawa R, Miyoshi Y, Muroya K, Kondoh T, Numakura C, Sato S, Nakabayashi K, Tayama C, Hata K, Sano S, Matsubara K, Kagami M, Yamazawa K, Ogata T. Molecular and clinical studies in 138 Japanese patients with Silver-Russell syndrome.PLoS One. 2013; 8: e60105.
Bliek J, Terhal P, van den Bogaard MJ, Maas S, Hamel B, Salieb-Beugelaar G, Simon M, Letteboer T, van der Smagt J, Kroes H, Mannens M. Hypomethylation of the H19 gene causes not only Silver-Russell syndrome (SRS) but also isolated asymmetry or an SRS-like phenotype. Am J Hum Genet. 2006; 78: 604-14.
Bruce S, Hannula-Jouppi K, Peltonen J, Kere J, Lipsanen-Nyman M. Clinically distinct epigenetic subgroups in Silver-Russell syndrome: the degree of H19 hypomethylation associates with phenotype severity and genital and skeletal anomalies.J Clin Endocrinol Metab. 2009; 94: 579-87.
Wakeling EL, Amero SA, Alders M, Bliek J, Forsythe E, Kumar S, Lim DH, MacDonald F, Mackay DJ, Maher ER, Moore GE, Poole RL, Price SM, Tangeraas T, Turner CL, Van Haelst MM, Willoughby C, Temple IK, Cobben JM. Epigenotype-phenotype correlations in Silver-Russell syndrome. J Med Genet. 2010; 47: 760-8.
Lee MP, DeBaun M, Randhawa G, Reichard BA, Elledge SJ, Feinberg AP. Low frequency of p57KIP2 mutation in Beckwith-Wiedemann syndrome. Am J Hum Genet. 1997; 61: 304-9.
Arboleda VA, Lee H, Parnaik R, Fleming A, Banerjee A, Ferraz-de-Souza B, Délot EC, Rodriguez-Fernandez IA, Braslavsky D, Bergadá I, Dell’Angelica EC, Nelson SF, Martinez-Agosto JA, Achermann JC, Vilain E. Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet. 2012; 44: 788-92.
Brioude F, Oliver-Petit I, Blaise A, Praz F, Rossignol S, Jule ML, Thibaud N, Faussat AM, Tauber M, Bouc YL, Netchine I. CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome. J Med Genet. 2013; 50: 823-30.
Hannula K, Kere J, Pirinen S, Holmberg C, Lipsanen-Nyman M. Do patients with maternal uniparental disomy for chromosome 7 have a distinct mild Silver-Russell phenotype? J Med Genet. 2001; 38: 273-8.
Sheridan MB, Bytyci Telegrafi A, Stinnett V, Umeh CC, Mari Z, Dawson TM, Bodurtha J, Batista DA. Myoclonus-dystonia and Silver-Russell syndrome resulting from maternal uniparental disomy of chromosome 7.Clin Genet. 2013; 84: 368-72.
Binder G, Liebl M, Woelfle J, Eggermann T, Blumenstock G, Schweizer R. Adult height and epigenotype in children with Silver-Russell syndrome treated with GH. Horm Res Paediatr. 2013; 80: 193-200.
Azzi S, Rossignol S, Steunou V, Sas T, Thibaud N, Danton F, Le Jule M, Heinrichs C, Cabrol S, Gicquel C, Le Bouc Y, Netchine I. Multilocus methylation analysis in a large cohort of 11p15-related foetal growth disorders (RussellSilver and Beckwith Wiedemann syndromes) reveals simultaneous loss of methylation at paternal and maternal imprinted loci. Hum Mol Genet. 2009; 18: 4724-33.
Court F, Martin-Trujillo A, Romanelli V, Garin I, Iglesias-Platas I, Salafsky I, Guitart M, Perez de Nanclares G, Lapunzina P, Monk D. Genome-wide allelic methylation analysis reveals disease-specific susceptibility to multiple methylation defects in imprinting syndromes.Hum Mutat. 2013; 34: 595-602.
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