Silver-Russell Syndrome

A number sign (#) is used with this entry because 20 to 60% of cases of Silver-Russell syndrome (SRS) are caused by the epigenetic changes of DNA hypomethylation at the H19/IGF2-imprinting control region (ICR1; 616186) on chromosome 11p15.5. ICR1 regulates the imprinted expression of H19 (103280) and IGF2 (147470). About 10% of SRS cases are due to maternal uniparental disomy of chromosome 7 (summary by Penaherrera et al., 2010).

Description

Silver-Russell syndrome is a clinically heterogeneous condition characterized by severe intrauterine growth retardation, poor postnatal growth, craniofacial features such as a triangular shaped face and a broad forehead, body asymmetry, and a variety of minor malformations. The phenotypic expression changes during childhood and adolescence, with the facial features and asymmetry usually becoming more subtle with age. Hypomethylation at distal chromosome 11p15 (ICR1) represents a major cause of the disorder. Opposite epimutations, namely hypermethylation at the same region on 11p15, are observed in about 5 to 10% of patients with Beckwith-Wiedemann syndrome (BWS; 130650), an overgrowth syndrome (Bartholdi et al., 2009).

Clinical Features

Silver-Russell syndrome (SRS) was reported independently by Silver et al. (1953) and Russell (1954). Silver et al. (1953) described 2 unrelated children with congenital hemihypertrophy, low birth weight, short stature, and elevated urinary gonadotropins. Russell (1954) described 5 unrelated children with intrauterine growth retardation and characteristic facial features, including triangular shaped face with a broad forehead and pointed, small chin with a wide, thin mouth. Two children had body asymmetry. Although each of these authors emphasized different phenotypic features, the whole picture was later identified as the 'Russell-Silver syndrome' (Patton, 1988).

Chitayat et al. (1988) described hepatocellular carcinoma in a 4-year-old boy with Russell-Silver syndrome. His brother had low birth weight and bilateral clinodactyly of the fifth fingers and grew slowly. Neither brother showed asymmetry. Donnai et al. (1989) described unusually severe Silver-Russell syndrome in 3 children with pre- and postnatal growth deficiency.

Price et al. (1999) reevaluated 57 patients in whom the diagnosis of SRS had been considered definite or likely. In 50 patients the clinical findings complied with a very broad definition of SRS. Notable additional findings included generalized camptodactyly in 11 individuals, many with distal arthrogryposis. Thirteen of the 25 males studied required genital surgery for conditions including hypospadias and inguinal hernia. Severe feeding problems were reported by 56% of parents, and sweating and pallor were described by 52% of parents in the early weeks of life. Fourteen of the 38 individuals of school age had been considered for special education; 4 attended special school. Molecular analysis in 42 subjects identified uniparental disomy (UPD) of chromosome 7 in 4 subjects. The phenotype in these 4 cases was generally milder than that in the non-UPD cases, with only 2 having the classic facial dysmorphism.

Anderson et al. (2002) conducted a study of gastrointestinal complications of SRS by questionnaire distributed by MAGIC, a support group for individuals with SRS. One-hundred thirty-five completed surveys were returned, of which 65 related to children with clear-cut SRS. Of these, 50 (77%) had gastrointestinal symptoms: gastroesophageal reflux disease (34%), esophagitis (25%), food aversion (32%), and failure to thrive (63%).

Gronlund et al. (2011) identified ophthalmologic abnormalities in 17 of 18 children with Silver-Russell syndrome. Best corrected visual acuity of the better eye was less than 0.1 log of the minimal angle of resolution (less than 20/200; legal blindness) in 11 children, and 11 children had refractive errors. Anisometropia (greater than 1 diopter) was noted in 3 children. Subnormal stereo acuity and near point of convergence were found in 2 of 16 children. The total axial length in both eyes was shorter compared with that of controls. Of 16 children, 3 had small optic discs, 3 had large cup:disc ratio, and 4 had increased tortuosity of retinal vessels. Gronlund et al. (2011) recommended ophthalmologic examination for children with SRS.

Inheritance

Rimoin (1969) described monozygotic male twins concordant for Silver dwarfism. However, Nyhan and Sakati (1976) and Samn et al. (1990) described monozygotic twins discordant for RSS. Bailey et al. (1995) described triplets, one of whom had RSS. The evidence was strong that he and his triplet brother were monozygotic; the brother was unaffected. The clinical characteristics consistent with RSS were a birth weight of less than 3 SD below the mean for gestational age and lower than either of his same-gestation sibs. The affected child had a small head circumference and a short birth length.

Fuleihan et al. (1971) observed 3 affected sibs among the 6 offspring of consanguineous Lebanese parents. Craniofacial disproportion and other minor anomalies were present. The mother was very short. Another possible familial occurrence was observed by Silver (cited by Gareis et al., 1971), who found that the mother of one of his cases was only 59 inches tall and had triangular facies and incurved fifth fingers. Tanner et al. (1975) reported on a longitudinal study of 39 cases. None of 61 sibs was affected. The authors found no distinction between Silver and Russell syndromes. Escobar et al. (1978) reported affected half brother and sister and reviewed reported familial cases.

Duncan et al. (1990) reported 7 affected persons in two 3-generation families. Three members of each family had an undergrowth of the left side of the body when compared with the normal right side. The authors noted that the clinical features were milder than those reported in sporadic cases. Duncan et al. (1990) found that in 17 reported families, multiple maternal relatives had complete or partial expression of Silver-Russell syndrome. Of 197 probands analyzed, 19% had one or more affected relatives. Two families with affected twins were consistent with new dominant mutation; possible autosomal recessive inheritance was found in 4 families. Because no male-to-male transmission was documented in 21 families in the literature or in the 2 families reported by Duncan et al. (1990), they suggested that X-linked dominant inheritance is a possibility.

Al-Fifi et al. (1996) reported 2 families with apparent autosomal dominant transmission of RSS. In 1 family, the mother (height 140 cm) and a son and daughter of hers were affected. The mother's father was remarkably short and thin until his late teens, but was later of normal height (25th centile) with triangular face, mild asymmetry, and prominent ears. In the second family, the mother's height and weight were below the third percentile for age before puberty. After puberty, her height reached the 25th percentile but she remained thin. A son and daughter were thought to be affected.

Ounap et al. (2004) described 2 sisters who met the criteria for SRS proposed by Price et al. (1999). The parents had normal facial features, normal height, and normal postnatal growth. Ounap et al. (2004) stated that this was the second well-documented case of familial recurrence of SRS suggesting autosomal recessive inheritance, the other being that of 6 sibs (5 males and 1 female) of normal first-cousin Arab parents (Teebi, 1992). In the family reported by Ounap et al. (2004), Bartholdi et al. (2009) identified hypomethylation at chromosome 11p15. Bartholdi et al. (2009) also reported another family in which 2 sibs had SRS associated with hypomethylation at 11p15. The authors postulated germ cell mosaicism of an incorrect methylation mark at the ICR1 during spermatogenesis in the fathers.

Bartholdi et al. (2009) reported a father and daughter with SRS who both had partial hypomethylation at chromosome 11p15, suggesting vertical transmission. Although the mechanism was difficult to explain, the authors postulated that the missing methylation mark in the father was not reset or corrected (setting of a methylation mark) during spermatogenesis. The findings had implications for genetic counseling.

Diagnosis

On the basis of radiographs of 15 patients, Herman et al. (1987) concluded that no single finding is pathognomonic; however, between the ages of 2 and 10 years, delayed maturation, clinodactyly, fifth middle or distal phalangeal hypoplasia, ivory epiphyses, and a second metacarpal pseudoepiphysis are suggestive.

Price et al. (1999) proposed diagnostic criteria for SRS: (1) birth weight below or equal to -2 SD from the mean; (2) poor postnatal growth below or equal to -2 SD from the mean at diagnosis; (3) preservation of occipitofrontal head circumference (OFC); (4) classic facial phenotype; and (5) asymmetry. Price et al. (1999) noted that some cases associated with uniparental disomy (UDP) (see below) might remain undiagnosed if strict criteria are applied, and suggested that the presence of feeding difficulties may be particularly helpful in making a diagnosis in these cases.

Cytogenetics

Chromosome 17

Ramirez-Duenas et al. (1992) observed severe Russell-Silver syndrome in a girl with translocation t(17;20)(q25;q13). No evidence of imbalance was found. The father exhibited the same balanced translocation. Ramirez-Duenas et al. (1992) questioned whether the RSS locus is located on either chromosome 17 or 20 and whether the patient's phenotype resulted from either unmasking of heterozygosity or genomic imprinting via paternal disomy. Midro et al. (1993) found the identical chromosome 17 breakpoint (17q25) in an 8-year-old boy with a de novo t(1;17)(q31;q25) and Silver-Russell syndrome.

In a child with RSS, Eggermann et al. (1998) reported a heterozygous paternally inherited deletion of the gene encoding chorionic somatomammotropin hormone (CSH1; 150200), which maps to 17q22-q24. The authors noted that deletions of CSH1 with no phenotypic consequences have been reported; however, a role for the heterozygous deletion in this case was considered possible.

Dorr et al. (2001) prepared a physical and transcript map of the critical region for the RSS translocation breakpoint on 17q23-q24.

Chromosome 7

Eggerding et al. (1994) noted that 3 cases of maternal uniparental disomy for chromosome 7 (mUPD7) had been reported in patients with intrauterine and postnatal growth retardation. Two patients were detected because they were homozygous for a cystic fibrosis mutation for which only the mother was heterozygous (see 219700). One patient was found because he was homozygous for a rare COL1A2 mutation (120160.0030). Eggerding et al. (1994) reported a female child with growth retardation in whom the normal chromosome 7 homologs were replaced by isochromosomes of 7p and 7q. Molecular studies showed that the child had paternal 7p isodisomy and maternal 7q isodisomy. Phenotypically, she had triangular facies, mild clinodactyly, and limb asymmetry. The authors suggested that imprinting may play a role.

Kotzot et al. (1995) investigated 35 patients with either Silver-Russell syndrome or primordial growth retardation and their parents with PCR markers to search for UPD7. Maternal disomy was found in 4 of the 35 patients, including 3 with isodisomy and 1 with heterodisomy. The data confirmed the localization of 1 or more maternally imprinted genes on chromosome 7. In a prospective study of 33 patients with sporadic Russell-Silver syndrome, Preece et al. (1997) studied the parent of origin of chromosome 7 using variable number tandem repeat (VNTR) or microsatellite repeat markers and identified 2 patients with maternal UPD of chromosome 7. The probands' condition was clinically mild and symmetrical, and showed no gross clinical differences from that of the 30 patients with chromosome 7 derived from both parents. Eggermann et al. (1997) studied 37 patients with Silver-Russell syndrome using short tandem repeat markers from chromosomes 2, 7, 9, 14, and 16. Uniparental disomy for chromosome 7 was detected in 3 SRS patients. In all 3 cases, it was maternal in origin. In 1 of the 3 families, complete isodisomy was found, and in the other 2 families, the allelic patterns were consistent with partial and complete heterodisomy, respectively. Short tandem repeat typing for uniparental disomy for chromosomes 2, 9, 14, and 16 was unrevealing. All 3 cases with maternal UPD7 had typical clinical features of SRS, with 2 of them classified as moderately severe. One was treated with human growth hormone with good results.

Dupont et al. (2002) reported a case of SRS in a child with an apparently balanced, maternally-inherited reciprocal translocation, t(7;16)(q21;q24), and maternal heterodisomy for chromosome 7. Microsatellite analysis showed a normal biparental inheritance of chromosome 16 but confirmed maternal heterodisomy of chromosome 7. The child presented with growth retardation and minor facial dysmorphism without mental retardation.

Monk et al. (2002) estimated that approximately 10% of SRS cases showed maternal uniparental disomy for chromosome 7. They suggested that the phenotype in these cases may be due to disruption of imprinted gene expression, as opposed to the unmasking of a mutant recessive allele. Monk et al. (2002) described 2 SRS patients and 4 probands with pre- and postnatal growth restriction with a range of cytogenetic disruptions of chromosome 7p, including duplications, pericentric inversions, and a translocation. In these 6 novel cases, and 3 previously described probands with duplications, Monk et al. (2002) mapped the breakpoints using FISH probes from a contig of PACs and BACs constructed from the centromere to 7p14. They identified a common breakpoint region within 7p11.2 in all 9 cases, pinpointing this specific interval. They also studied the imprinting status of genes within the 7p14-p11.1 region flanked by the most extreme breakpoints.

By examining 77 families with SRS, Nakabayashi et al. (2002) identified 2 patients with de novo chromosomal rearrangements involving the short arm of chromosome 7. One patient had a partial duplication and was cytogenetically characterized 46,XX,dup(7)(p12p14), and the other patient had a paracentric inversion and was characterized 46,XY,inv(7)(p14p21). The duplication breakpoint interrupted the C7ORF10 gene (609187), and the inversion breakpoint mapped to the 5-prime end of the C7ORF10 gene, possibly just within intron 1. However, Nakabayashi et al. (2002) suggested that the inversion breakpoint may affect both C7ORF10 and C7ORF11, since the 2 genes are separated by less than 100 bp.

Guettard et al. (2008) reported a 35-year-old man with myoclonus-dystonia (159900) and Silver-Russell syndrome. He developed symptoms of myoclonus-dystonia at age 17. Features of SRS included intrauterine growth retardation, short stature, and facial dysmorphism. He did not have mental retardation. Cytogenetic analysis identified mosaicism for a small supernumerary ring chromosome 7, which was considered unlikely to contribute to the phenotype. Microsatellite analysis indicated loss of the paternal allele and maternal UPD7 with maternally imprinted loss of SGCE gene (604149) expression. The findings indicated UPD7 resulted in repression of both alleles of the maternally imprinted SGCE gene, suggesting loss of function of SGCE as the disease mechanism in myoclonus-dystonia. Guettard et al. (2008) suggested that some patients with SRS and similar cytogenetic abnormalities may develop symptoms of myoclonus-dystonia.

Penaherrera et al. (2010) found that 3 of 35 blood samples from patients with SRS had maternal UPD7. All were highly methylated at the SGCE promoter.

Chromosome 1

Van Haelst et al. (2002) reported a patient with phenotypic features of Silver-Russell syndrome who had trisomy 1q32.1-q42.1.

Chromosome X

Li et al. (2004) reported a female infant with a karyotype of 45,X on prenatal amniocytes. After delivery she was noted to have features consistent with Russell-Silver syndrome, including a triangular face with prominent forehead, large eyes, a thin nose, malar hypoplasia, thin upper lip with downturned corner of the mouth, and a pointed chin. Marked body asymmetry was evident at birth, with the left side significantly smaller than the right side. She also had a diphalangeal left fifth finger. Skin fibroblast culture and analysis showed a karyotype of 45,X on the right side and 45,X/46,XX on the left side. The case is another illustration of the genetic heterogeneity of the Russell-Silver phenotype.

Chromosome 11

Chiesa et al. (2012) described 2 maternal 11p15.5 microduplications with contrasting phenotypes. In the first case, a 1.2-Mb inverted duplication of chromosome 11p15 derived from the maternal allele resulted in Silver-Russell syndrome. The duplication encompassed the entire 11p15.5 imprinted gene cluster, and hypermethylation of CpGs throughout the ICR2 region was observed. These findings were consistent with the maintenance of genomic imprinting, with a double dosage of maternal imprinting and resulting in a lack of KCNQ1OT1 (604115) transcription. In the second case, a maternally inherited 160-kb inverted duplication that included only ICR2 and the most 5-prime 20 kb of KCNQ1OT1 resulted in a BWS (130650) phenotype in 5 individuals in 2 generations. This duplication was associated with hypomethylation of ICR2 resulting from partial loss of the imprinted methylation of the maternal allele, expression of a truncated KCNQ1OT1 transcript, and silencing of CDKN1C (600856). Chromatin RNA immunopurification studies suggested that the KCNQ1OT1 RNA interacts with chromatin through its most 5-prime 20-kb sequence, providing a mechanism for the silencing activity of this noncoding RNA. The finding of similar duplications of ICR2 resulting in different methylation imprints suggested that the ICR2 sequence is not sufficient for establishing DNA methylation on the maternal chromosome, and that some other property, possibly orientation-dependent, is needed.

Molecular Genetics

Abu-Amero et al. (2008) provided a review of the complex genetic etiology of Silver-Russell syndrome, which primarily involves chromosomes 7 and 11.

Genes on Chromosome 7

In the mouse, and presumably the human as well, the gene encoding growth factor receptor-bound protein-10 (GRB10; 601523) is imprinted. GRB10 protein binds to the insulin receptor (INSR; 147670) and IGF1R via its Src homology 2 domain and inhibits the associated tyrosine kinase activity that is involved in the growth-promoting activities of insulin (INS; 176730) and insulin-like growth factors I (IGF1; 147440) and II (IGF2; 147470). The mouse Grb10 gene is located on proximal chromosome 11. Miyoshi et al. (1998) suggested that, in the mouse, Grb10 is responsible for the imprinted effects of prenatal growth retardation or growth promotion caused by maternal or paternal duplication of proximal chromosome 11 with reciprocal deficiencies, respectively. Based on the location of the human GRB10 gene on 7p12-p11.2 and reports that maternal uniparental disomy 7 may be responsible for Russell-Silver syndrome, Miyoshi et al. (1998) identified GRB10 as a candidate gene for the disorder.

Joyce et al. (1999) estimated that approximately 10% of cases of SRS are associated with maternal uniparental disomy of chromosome 7, suggesting that at least one imprinted gene on chromosome 7 is involved in the pathogenesis of the disease. They reported a proximal 7p interstitial inverted duplication in a mother and daughter, both of whom had features of SRS, including markedly short stature, low birth weight, facial asymmetry, and fifth finger clinodactyly. Fluorescence in situ hybridization with YAC probes enabled delineation of the duplicated region as 7p13-p12.1. This region of proximal 7p is known to be homologous to an imprinted region in mouse chromosome 11 and contains the growth-related genes GRB10, epidermal growth factor receptor (EGFR; 131550), and insulin-like growth factor-binding protein-1 (IGFBP1; 146730), all of which had been suggested as candidate genes for SRS. Molecular analysis in the case of Joyce et al. (1999) showed that the duplication in both mother and daughter spanned a distance of approximately 10 cM and included GRB10 and IGFBP1 but not EGFR. The de novo duplication in the mother was shown to be of paternal origin. To test the hypothesis that submicroscopic duplications of 7p, whether maternal or paternal in origin, are responsible for at least some cases of SRS, they screened a further 8 patients and found duplications of either GRB10 or IGFBP1. The results were thought to suggest that imprinted genes may not underlie the SRS phenotype. Joyce et al. (1999) proposed an alternative hypothesis to explain the occurrence of maternal UPD7 in some cases of SRS. They suggested that SRS may be caused by the inheritance of an additional copy of chromosome 7 material, either as a result of small duplications or undetected trisomy. They pointed out that 6 cases of maternal UPD7 had been shown to have arisen by trisomy rescue. They considered it possible that all cases of maternal UPD7 arise in this way and that an additional copy of the SRS gene(s) in an undetected trisomic cell line is responsible for the phenotype. Somatic mosaicism might help account for the asymmetric growth patterns often seen in SRS, a mechanism implicated in the hemihypertrophy observed in Beckwith-Wiedemann syndrome (130650).

In a study of genetic and phenotypic similarities among patients exhibiting developmental verbal dyspraxia (DVD; 602081), Feuk et al. (2006) studied 7 cases of Russell-Silver syndrome with maternal UPD7. All showed absence of a paternal copy of FOXP2 (605317). All had marked speech delay and difficulties in speech output, particularly articulation. Feuk et al. (2006) considered it noteworthy that while SRS is clinically and genetically heterogeneous, mainly only patients with complete maternal UPD7 (approximately 10%) exhibit DVD. These and other observations suggested that absence of paternal FOXP2 is the cause of DVD in SRS.

Wakeling et al. (2000) studied the imprinting status of IGFBP1 and IGFBP3 (146732) in normal fetuses and in patients with SRS. Biallelic expression of both genes was found in normal fetal tissue and in 2 SRS patients with UPD7 and 4 SRS patients without UPD7. Wakeling et al. (2000) concluded that IGFBP1 and IGFBP3 were unlikely to be involved in SRS.

Monk et al. (2000) identified a de novo duplication of 7p13-p11.2 in a 5-year-old girl with features characteristic of SRS. FISH confirmed the presence of a tandem duplication encompassing the GRB10, IGFBP1, and IGFBP3 genes, but not the EGFR gene. Microsatellite markers showed that the duplication was of maternal origin. These findings provided the first evidence that SRS may result from overexpression of a maternally expressed imprinted gene, rather than from absent expression of a paternally expressed gene. The GRB10 gene lies within the duplicated region and was considered to be a strong candidate, since it is a known growth repressor. Monk et al. (2000) demonstrated that the GRB10 genomic interval replicates asynchronously in human lymphocytes, suggestive of imprinting. An additional 36 SRS probands were investigated for duplication of GRB10, but none was found. However, it remained possible that GRB10 and/or other genes within 7p13-p11.2 are responsible for some cases of SRS.

Yoshihashi et al. (2000) performed mutation analysis of the GRB10 gene in 58 unrelated patients with SRS and identified a pro95-to-ser substitution within the N-terminal domain in 2 of the patients. However, Hannula et al. (2001), Hitchins et al. (2001), and McCann et al. (2001) presented evidence creating uncertainty about the role of the GRB10 gene in Russell-Silver syndrome.

Among 11 patients with RSS, Martinez et al. (2001) found no molecular evidence for duplication of chromosomal segment 7p11.2-p13.

Hannula et al. (2001) studied 4 patients with maternal UPD7 and argued that they might compose a distinct phenotypic entity among Silver-Russell syndrome patients with a mild phenotype. In a systematic screening with microsatellite markers for maternal UPD of chromosome 7 in patients with SRS, Hannula et al. (2001) identified a patient with a small segment of matUPD7 (7q31-qter) and biparental inheritance of the remainder of the chromosome. The pattern was thought to be explained by somatic recombination in the zygote. The matUPD7 segment extended for 35 Mb and included the imprinted gene cluster of PEG1/MEST (601029) and COPG2 (604355) at 7q32. GRB10 at 7p12-p11.2 was located within the region of biparental inheritance in this case.

Hitchins et al. (2001) used expressed polymorphisms to determine the imprinting status of the GRB10 gene in multiple human fetal tissues. Expression from the paternal allele was exclusive in the spinal cord and predominant in fetal brain, whereas expression from both parental alleles was detected in a wide range of other organs and peripheral tissues. The role GRB10 might play in the etiology of RSS involving chromosome 7 was difficult to predict in view of the imprinting profile of the gene. Further doubt about the role of GRB10 in RSS was cast by the absence of mutations detected by sequencing in 18 classic RSS patients, where major structural chromosomal abnormalities and matUPD7 had previously been excluded. McCann et al. (2001) likewise cast doubt on the role of GRB10 in Silver-Russell syndrome. Using RT-PCR, they confirmed that GRB10 imprinting in brain and muscle is isoform specific, and they demonstrated absence of imprinting in growth plate cartilage, the tissue most directly involved in linear growth. Thus, they considered it unlikely that GRB10 is the gene responsible for SRS.

Genes on Chromosome 11

Given the crucial role of the 11p15 imprinted region in the control of fetal growth, Gicquel et al. (2005) hypothesized that dysregulation of genes at 11p15 might be involved in syndromic intrauterine growth retardation. In the telomeric imprinting center region ICR1 of the 11p15 region in several individuals with clinically typical Silver-Russell syndrome, they identified an epimutation (demethylation). The epigenetic defect was associated with, and probably responsible for, relaxation of imprinting and biallelic expression of H19 (103280) and downregulation of IGF2 (147470). These findings provided new insight into the pathogenesis of SRS and strongly suggested that the 11p15 imprinted region, in addition to the imprinted region of 7p13-p11.2 and 7q31-qter, is involved in SRS. The loss of paternal methylation in individuals with SRS may have resulted from a deficient acquisition of methylation during spermatogenesis or from a lack of maintenance of methylation after fertilization. The 5 individuals with SRS that carried the epimutation had only a partial loss of methylation, and 4 of them had body asymmetry. These data suggested that the loss of methylation occurred after fertilization and resulted in a mosaic distribution of the epimutation.

The epimutation described in individuals with SRS by Gicquel et al. (2005) is the exact opposite of one of the molecular defects responsible for Beckwith-Wiedemann syndrome (BWS; 130650): approximately 10% of individuals with BWS have hypermethylation of the H19 promoter. The most common epimutation in individuals with BWS involves the centromeric 11p15 subdomain and consists of loss of methylation of the maternal KCNQ1OT1 (604115) allele. Paternal inheritance of a null KCNQ1OT1 allele results in fetal growth retardation by 20 to 25% but does not affect expression of H19 or IGF2. One of the 5 individuals with the epimutation was a monozygotic twin, and her twin had no clinical features of SRS. Both twins had a loss of methylation in the telomeric 11p15 domain in their leukocyte DNA and biallelic expression of H19 in their blood cells. However, in skin fibroblasts, only the affected twin showed abnormal methylation. This observation was consistent with results obtained from BWS-discordant monozygotic twins and suggested that the presence of the epigenetic defect of blood cells of both twins results from shared fetal circulation.

The H19 differentially methylated region (DMR) controls the allele-specific expression of both the imprinted H19 tumor suppressor gene and the IGF2 growth factor. Hypermethylation of this DMR--and subsequently of the H19 promoter region--is a major cause of the clinical features of gigantism and/or asymmetry seen in Beckwith-Wiedemann syndrome or in isolated hemihypertrophy. Bliek et al. (2006) reported a series of patients with hypomethylation of the H19 locus. The main clinical features of asymmetry and growth retardation were the opposite of those seen in patients with hypermethylation of this region. In addition, they found that complete hypomethylation of the H19 promoter was associated in 2 of 3 patients with the full clinical spectrum of Silver-Russell syndrome.

Following up on the work of Gicquel et al. (2005) on epigenetic mutations in the etiology of SRS, Eggermann et al. (2006) screened a cohort of 51 SRS patients for epimutations in ICR1 (the telomeric imprinting center region of 11p15) and KCNQ1OT1 (604115) by methylation-sensitive Southern blot analyses. ICR1 demethylation was observed in 16 of the 51 SRS patients, corresponding to a frequency of approximately 31%. Changes in methylation at the KCNQ1OT1 locus were not detected. Combining these data with those on maternal duplications in 11p15, nearly 35% of SRS cases are associated with detectable (epi)genetic disturbances in 11p15. Eggermann et al. (2006) suggested that a general involvement of 11p15 changes in growth-retarded patients with only minor or without further dysmorphic features must be considered. SRS and BWS may be regarded as 2 diseases caused by opposite (epi)genetic disturbances of the same chromosomal region displaying opposite clinical pictures.

Schonherr et al. (2007) stated that methylation defects in the imprinted region of 11p15 can be detected in about 30% of patients with SRS. They reported the first patient with SRS with a cryptic duplication restricted to the centromeric imprinting center ICR2 in 11p15. The maternally inherited duplication in this patient included a region of 0.76 to 1.0 Mbp and affected the genes regulated by the ICR2, among them CDKN1C (600856) and LIT1 (604115).

Netchine et al. (2007) screened for 11p15 epimutation and mUPD7 in SRS and non-SRS small-for-gestational-age (SGA) patients to identify epigenetic-phenotypic correlations. Of the 127 SGA patients studied, 58 were diagnosed with SRS; 37 of these (63.8%) displayed partial loss of methylation (LOM) of the 11p15 ICR1 domain, and 3 (5.2%) had mUPD7. No molecular abnormalities were found in the non-SRS SGA group. Birth weight, birth length, and postnatal body mass index (BMI) were lower in the abnormal 11p15 SRS group (ab-ICR1-SRS) than in the normal 11p15 SRS group (-3.4 vs -2.6 SD score (SDS), -4.4 vs -3.4 SDS, and -2.5 vs -1.6 SDS, respectively; p less than 0.05). Among SRS patients, prominent forehead, relative macrocephaly, body asymmetry, and low BMI were significantly associated with ICR1 LOM. All ab-ICR1-SRS patients had at least 4 of 5 criteria of the scoring system. Netchine et al. (2007) concluded that the 11p15 ICR1 epimutation is a major, specific cause of SRS exhibiting failure to thrive. They proposed a clinical scoring system (including a BMI of less than -2 SDS), highly predictive of 11p15 ICR1 LOM, for the diagnosis of SRS.

Bullman et al. (2008) reported a patient with SRS who had mosaic maternal uniparental disomy of chromosome 11 with abnormal methylation of ICR2. MLPA analysis showed 12 informative loci between chromosome 11p15.5 to 11q23.3. The isodisomy was the reciprocal of the mosaic paternal isodisomy seen in patients with BWS.

Azzi et al. (2009) studied the methylation status of 5 maternally and 2 paternally methylated loci in a series of 167 patients with 11p15-related fetal growth disorders. Seven of 74 (9.5%) Russell-Silver (RSS) patients and 16 of 68 (24%) Beckwith-Wiedemann (BWS; 130650) patients showed multilocus loss of methylation (LOM) at regions other than ICR1 and ICR2 11p15, respectively. Moreover, over two-thirds of multilocus LOM RSS patients also had LOM at a second paternally methylated locus, DLK1/GTL2 IG-DMR. No additional clinical features due to LOM of other loci were found, suggesting an (epi)dominant effect of the 11p15 LOM on the clinical phenotype for this series of patients. Surprisingly, 4 patients displayed LOM at both ICR1 and ICR2 11p15; 3 of them had a RSS and 1 patient had a BWS phenotype. The authors concluded that multilocus LOM can also concern RSS patients, and that LOM can involve both paternally and maternally methylated loci in the same patient.

Using PCR-based methylation analysis, Penaherrera et al. (2010) found that 13 (37%) of 35 blood samples from patients with SRS showed methylation levels at H19/IGF2 ICR1 that were more than 2 SD below the mean for controls. Clinically, SRS patients had a lower birth weight (at least 2 SD below the mean), relative macrocephaly, and a higher frequency of body asymmetry compared to SRS patients without these epigenetic changes. One patient had a mediastinal neuroblastoma. Controls had considerable variability in methylation (30 to 47%) at ICR1, which Penaherrera et al. (2010) noted can cause some ambiguity in establishing clear cutoffs for diagnosis.

Other Genes

Penaherrera et al. (2010) found no changes in methylation of the KVDMR1 (see KCNQ1; 607542), PLAGL1 (603044), or PEG10 (609810) genes in blood samples of 35 patients with SRS. Whole genome methylation analysis of a subset of 22 SRS patients, including 10 who had hypomethylation at ICR1, showed no global disruption in methylation in these patients compared to controls.

Exclusion Studies

Previous studies had shown that individuals with a deletion of 15q26.1-qter, which includes the insulin-like growth factor I receptor gene (IGF1R; 147370), may exhibit some phenotypic characteristics resembling those of Russell-Silver syndrome. Abu-Amero et al. (1997) investigated 33 RSS probands, with normal karyotypes, and their parents for the presence of both copies of IGF1R by gene dosage analysis of Southern blot hybridization. All 33 probands had both copies of the gene. Two important functional regions of IGF1R were also investigated for DNA mutations using SSCP analysis; no mutations were found. The patients were from the series of cases studied by Preece et al. (1997).

Genotype/Phenotype Correlations

Binder et al. (2008) compared the genotype in 44 patients with SRS with the endocrine phenotype. Epimutations at 11p15 were found in 19 of the 44, UPD7 in 5, and small structural aberrations of the short arm of chromosome 11 in 2. Of the 44 cases, 18 were negative for any genetic defect known (41%). The most severe phenotype was found in children with 11p15 SRS. Children with UPD7 SRS had a significantly higher birth length than the 11p15 SRS subjects (P less than 0.004) but lost height SD score postpartum, whereas children with 11p15 SRS showed no change in height SD score. There was a trend toward more height gain in children with UPD7 than in those with 11p15 epimutation under GH therapy (+2.5 vs +1.9 height SD score after 3 years) (P = 0.08). Binder et al. (2008) concluded that children with SRS and an 11p15 epimutation have IGFBP3 (146732) excess and show endocrine characteristics suggesting IGF1 (147440) insensitivity, whereas children with SRS and UPD7 were not different with respect to endocrine characteristics from nonsyndromic short children born SGA. This phenotype-genotype correlation implicated divergent endocrine mechanisms of growth failure in SRS.

Bartholdi et al. (2009) found that 106 (53%) of 201 patients with suspected SRS actually fulfilled clinical criteria for the disorder. Hypomethylation at the ICR1 on chromosome 11p15 was observed in 41 (38.5%) of the 106 patients. The majority of patients showed hypomethylation of both H19 and IGF2, but 10 showed selective hypomethylation of H19 and 2 showed selective hypomethylation of IGF2. However, the authors noted that the IGF2-specific probe showed a broader variation in controls as compared to the H19 probe. Seven (6.6%) of the 106 patients had uniparental disomy of chromosome 7. Patients carrying epimutations had higher disease scores than those with maternal uniparental disomy of chromosome 7 or those with no identified defects, indicating that hypomethylation at 11p15 was associated with a more severe phenotype, particularly body asymmetry. No genetic anomaly was detected in 54.7% of patients.

History

Tanner and Ham (1969) suggested that the designation 'Silver dwarf' be reserved for children of short stature and low birth weight who have asymmetry of arms, legs, body or head, and incurved fifth fingers. They suggested that the designation 'Russell dwarf' be reserved for the similar situation when asymmetry is lacking. Patton (1988) noted that this distinction had not been generally accepted.