Clinical Diagnosis

The clinical diagnosis of RSS depends on the presence of intrauterine growth retardation accompanied by postnatal growth deficiency [Silver et al 1953, Russell 1954, Price et al 1999]. No signs or features are pathognomonic for RSS.

Although several helpful diagnostic scoring systems have been developed for RSS, the more recent studies of Netchine et al [2007] and Bartholdi et al [2009] focused primarily on phenotypic findings of individuals with 11p15.5 methylation abnormalities (see Testing). Furthermore, many persons with RSS lack typical clinical features and have a more subtle presentation, an observation supported by the studies of Eggermann et al [2009] that identified growth retardation, asymmetry, and prominence of the forehead that was milder than usual in persons with RSS who had 11p15.5 epimutations. Wakeling et al [2010] also showed that the clinical features of RSS are not consistent in all persons.

The following criteria, compiled from information included in the studies of Netchine et al [2007], Bartholdi et al [2009], Eggermann et al [2009], and Wakeling et al [2010], indicate that the diagnosis of RSS and supportive laboratory testing should be considered in individuals who have three major criteria or two major and two minor criteria.

• Major criteria

  • Intrauterine growth retardation/small for gestational age (<10th percentile)

  • Postnatal growth with height/length <3rd percentile

  • Normal head circumference (3rd-97th percentile)

  • Limb, body, and/or facial asymmetry

• Minor criteria

  • Short (arm) span with normal upper- to lower-segment ratio

  • Fifth finger clinodactyly

  • Triangular facies

  • Frontal bossing/prominent forehead

• Supportive criteria

  • Café au lait spots or skin pigmentary changes

  • Genitourinary anomalies (cryptorchidism, hypospadias)

  • Motor, speech, and/or cognitive delays

  • Feeding disorder

  • Hypoglycemia

Russell-Silver syndrome (RSS) is a genetically heterogeneous condition (see Testing) with a consistent but variable phenotype: children with RSS demonstrate varying responses to growth hormone, variable late catch-up growth, and variable developmental outcomes

Testing

The two known causes of RSS are chromosome 11p15.5-related Russell-Silver syndrome and chromosome 7-related Russell-Silver syndrome

Chromosome 11p15.5-related Russell-Silver syndrome is associated primarily with abnormalities at an imprinted domain on chromosome 11p15.5 [Abu-Amero et al 2010]. The 11p15.5 chromosome region has a cluster of imprinted genes that play a critical role in fetal and placental growth. Genomic imprinting is a phenomenon whereby the DNA of each allele of a gene is differentially modified resulting in monoallelic expression of only one parental allele; the parental allele that is expressed is specific to each imprinted gene.

Imprinted genes often occur in clusters that include a regulatory imprinting center (IC). At one of the 11p15.5 imprinted clusters, parent-specific differential methylation of imprinting center 1 (IC1) regulates reciprocal expression of IGF2, which encodes a growth factor crucial for fetal development, and H19, a noncoding transcript (Figure 1A). In RSS, hypomethylation of IC1 leads to biallelic H19 expression and biallelic silencing of IGF2 resulting in growth restriction (Figure 1B). See Molecular Genetic Pathogenesis.

Figure

Figure 1. 11p15.5-Related Russell-Silver Syndrome. Schematic representation of the imprinting cluster

Diagram A. The chromosome 11p15.5 imprinting cluster is functionally divided into two domains:

Domain 1. Dysregulation (more...)

• Methylation analysis

  • Hypomethylation at IC1 on the paternal chromosome is detected in 30%-50% of individuals with RSS (Figure 1B). Because IC1 regulates methylation of IGF2 and H19, differential analysis showed that in most cases both of these genes are hypomethylated.

  • Because 11p15.5 hypomethylation at the paternal IC1 is a postzygotic event, most individuals with RSS have a somatic distribution of abnormal methylation patterns (see Table 1 for testing implications)

  • A small number of individuals with RSS have selective hypomethylation of only H19 or only IGF2 [Bartholdi et al 2009].

  • A small number of individuals with RSS have abnormal hypermethylation of IGF2R (the gene encoding the IGF2 receptor on chromosome 6q25-q27) with normal methylation of H19 [Turner et al 2010]. In these instances RSS may result from reduction of IGF2R, which functions to clear IGF2 from circulation thereby limiting its growth effects [Braulke 1999].

• Deletion/duplication analysis

  • A small number of individuals with RSS have a duplication involving the maternal 11p15.5 region. Larger duplications, which can involve translocations and inversions, can be detected by cytogenetic analysis [Fisher et al 2002, Eggermann et al 2005], but higher resolution deletion/duplication methods have greater sensitivity (Table 1). How maternal disomy of 11p15.5 results in RSS is unclear, but may involve the dosage of genes at the upstream CDKN1C imprinted cluster [Fisher et al 2002].

  • A maternally inherited duplication of imprinting center 2 (IC2) has been identified in one individual with RSS [Schönherr et al 2007]. The implications of this finding and its contribution to the number of cases with RSS are unclear, pending further study.

Chromosome 7-related Russell-Silver syndrome

• Maternal uniparental disomy of chromosome 7 (UPD7) has been implicated in 7%-10% of RSS [Moore et al 1999, Hannula et al 2001, Kim et al 2005]; however, the specific genetic loci responsible for UPD7 imprinting have not yet been delineated (see Molecular Genetic Pathogenesis).

  • Maternal isodisomy and maternal heterodisomy have been reported [Bernard et al 1999, Price et al 1999].

  • Mosaicism for UPD7 has been observed [Reboul et al 2006].

  • Segmental UPD7 has been observed: Hannula et al [2001] reported one case with maternal UPD for the region 7q31-qter; Eggermann [2008] reported two cases, both with UPD involving most of the long arm of chromosome 7 (7q11.2-qter).

• Rare chromosome 7 anomalies seen in individuals with RSS include the following:

  • Mosaic trisomy 7 in two children who had maternal uniparental heterodisomy for chromosome 7 [Flori et al 2005, Font-Montgomery et al 2005], one of whom was identified prenatally [Font-Montgomery et al 2005]

  • Interstitial deletion of the long arm of chromosome 7 [del(7)(q21.1q21.3)] in one child [Courtens et al 2005]

  • Submicroscopic duplication of 7p11.2-p12 identified by fluorescence in situ hybridization (FISH) (not visible by routine karyotyping; requires FISH or another technique that can detect deletions/duplications; see Table 1) [Joyce et al 1999, Monk et al 2000]

See Figure 1.

Research testing. Sequence analysis and screening for rearrangements for IC1, H19, and IGF2 are performed on a research basis only.

Table 1. Summary of Molecular Genetic Testing Used in Russell-Silver Syndrome

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RSS Type	Genetic Mechanism	Test Method	Mutations / Alterations Detected	Proportion of RSS Attributed to this Genetic Mechanism 1	Test Availability
Chromosome 11p15.5-related RSS	Loss of IC1 methylation of paternal 11p15.5	Methylation analysis	Hypomethylation of paternal IC1 2, 3	~35-50%	Clinical
	Duplication of maternal 11p15.5	Deletion / duplication analysis 4	11p15.5 duplications	Unknown
Chromosome 7-related RSS	UPD (maternal)	UPD analysis (various methods) 5	Chromosome 7 maternal disomy 6	~7%-10%	Clinical
	Deletion/ duplication	Deletion / duplication analysis, Cytogenetic analysis	Chromosome 7 anomalies	Rare

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect an alteration based on genetic mechanism and chromosomal location

2. False negatives may occur as a result of mosaicism, as 11p15.5 hypomethylation occurs post fertilization. Testing of tissue from a second source (e.g., buccal cells or fibroblasts) should be performed.

3. Methylation-specific 11p15.5 testing is not recommended for prenatal diagnosis, due to uncertainty of the timing of methylation of specific loci in the embryo.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

5. Various methods can detect UPD, for example: SNP or marker analysis, MS-MLPA (methylation specific multiplex ligation-dependent probe amplification). Testing may require parental blood specimens.

6. Mosaicism has been observed in cases of maternal UPD7 and other chromosome 7 rearrangements; testing of an alternate tissue source may be appropriate.

Testing Strategy

To confirm/establish the diagnosis in a proband. The recommended order of clinically available testing for RSS is the following:

• If RSS is suspected on clinical grounds, ordering methylation studies of IC1 at 11p15.5 and UPD7 studies simultaneously is most effective. Methylation studies would detect any 11p15.5 duplications or deletions. For the 11p15.5 region, MS-MLPA is the most robust testing methodology and can detect all three mechanisms: methylation abnormality, UPD11, and/or deletion/duplication of the region. If testing of lymphoblasts is negative, consider mosaicism in the patient and re-test other tissues (e.g., buccal cells).

• If clinical suspicion of RSS is low, deletion/duplication analysis with array genomic hybridization should be performed first. See array GH.

An algorithm for molecular genetic testing has been published by Eggermann et al [2010] (see full text article).

Genetically Related (Allelic) Disorders

Beckwith-Wiedemann syndrome is associated with abnormal regulation of gene transcription in the imprinted domain on chromosome 11p15.5 (also known as the BWS critical region).

Molecular alterations at 11p15 including loss of methylation at IC2, gain of methylation at IC1 [Martin et al 2005], and 11p15 paternal uniparental disomy [Shuman et al 2002] have been reported in individuals with isolated hemihyperplasia.

Somatic mosaicism for loss of methylation at the paternal IC1 is associated with isolated hemihypoplasia [Zeschnigk et al 2008, Eggermann 2009].

Isolated Wilms tumor can be associated with constitutional alterations of chromosome 11p15.5 including hypermethylation at IC1, paternal uniparental disomy of 11p15.5, and genomic abnormalities including microdeletion and microinsertion [Scott et al 2008].

Natural History

The most critical diagnostic clinical features [Price et al 1999]:

• Intrauterine growth retardation (IUGR): birth weight 2 SD or more below the mean

• Postnatal growth retardation: length or height 2 SD or more below the mean

• Normal head circumference, often with the appearance of "pseudohydrocephalus"

• Fifth-finger clinodactyly

• Limb-length asymmetry

Additional features that can aid in the diagnosis:

• Short stature with normal upper- to lower-segment ratio, normal skeletal survey, and frequently delayed bone age

• Typical facial phenotype of broad prominent forehead with small triangular face, small narrow chin, and down-turned corners of the mouth

• Hypoglycemia

• Brachydactyly, camptodactyly

• Café au lait spots

• Arm span less than height

Growth. The early problems for children with Russell-Silver syndrome (RSS) are generally related to growth and feeding. Children with RSS have intrauterine growth retardation with postnatal growth deficiency. Growth parameters with growth charts for European children with RSS have been published [Wollmann et al 1995]. Growth charts for North American children with RSS are available from the MAGIC Foundation.

Growth velocity is normal. In individuals with RSS not treated with growth hormone, the average adult height of males is 151.2 cm (-7.8 SD) and that of females is 139.9 cm (-9 SD) [Wollmann et al 1995].

Growth is expected to be proportionate, although most individuals with RSS have a short arm span compared to height with a normal upper- to lower-segment ratio [Silver et al 1953, Saal et al 1985].

See Management for use of growth hormone therapy to influence growth in children with RSS. Note: Many children with RSS do not achieve normal stature even with administration of human growth hormone.

Most children said to have RSS who have demonstrated catch-up growth in later childhood [Saal et al 1985] probably had conditions other than classic RSS.

Growth hormone deficiency. A study of 24 children with RSS found hypoglycemia in ten children; growth hormone insufficiency (as determined by glucagon stimulation testing) was found in several of the children and posited as one likely cause of the hypoglycemia [Azcona & Stanhope 2005].

Skeletal abnormalities in individuals with RSS are generally limited to limb-length asymmetry that, at least in some individuals, may be hemihypotrophy with diminished growth of the affected side.

Because it is used as a diagnostic criterion, fifth-finger clinodactyly is among the most frequently described skeletal anomalies in individuals with RSS.

In a systematic study of orthopedic manifestations in 25 individuals with RSS, 19 had metacarpal and phalangeal abnormalities, nine had scoliosis, five had toe syndactyly, and three had developmental dysplasia of the hips [Abraham et al 2004].

Neurodevelopment. Besides the growth issues, neurodevelopment is probably of greatest concern to parents. Despite reassurances about "normal intelligence" in individuals with RSS in earlier reports, evidence is increasing that children with this condition are at significant risk for developmental delay (both motor and cognitive) and learning disabilities.

• In a study of 20 children with RSS between ages six and 12 years, the average IQ was 86. In addition, 36% of these children required special education and 48% required speech therapy [Lai et al 1994]. The specific etiology of the RSS was not identified for any of the children studied.

• In another study, the average IQ in 36 children with RSS was 95.7 compared to 104.20 in sibling controls. Of note, the two children with maternal uniparental disomy for chromosome 7 had IQs of 81 and 84, respectively [Noeker & Wollmann 2004].

• In a review of a large cohort with either 11p15 methylation defects or maternal UPD7, mild developmental delays were more commonly seen in those with UPD77 compared to those with 11p15 methylation defects (65% vs. 20%). Speech delays were common in both groups [Wakeling et al 2010].

Hypoglycemia. Children with RSS have little subcutaneous fat, are quite thin, and often have poor appetites; they are at risk for hypoglycemia with any prolonged fast, including surgery [Tomiyama et al 1999]. In a study of children with RSS, contributing factors for hypoglycemia included reduced caloric intake, often secondary to poor appetite and feeding; reduced body mass; and, in several children, growth hormone deficiency [Azcona & Stanhope 2005]. While most children had clinical symptoms of hypoglycemia, especially diaphoresis (excessive sweating), several were asymptomatic.

Diaphoresis in early childhood may be associated with hypoglycemia, although diaphoresis may occur in the absence of hypoglycemia [Stanhope et al 1998].

Gastrointestinal disorders are common [Anderson et al 2002]. Problems include gastroesophageal reflux disease, esophagitis, food aversion, and failure to thrive. Some of these issues may be iatrogenic (i.e., related to treatments for poor growth). Reflux esophagitis should be suspected in children with either food aversion or aspiration.

Severe craniofacial anomalies are uncommon. Some individuals with RSS have Pierre Robin sequence and cleft palate. Wakeling et al [2010] found cleft palate or bifid uvula in 7% of their patients with 11p15.5 methylation defects and in no patients with maternal UPD7.

Dental and oral abnormalities are rare. Microdontia, high-arched palate, and dental crowding secondary to the relative micrognathia and small mouth have been reported [Cullen & Wesley 1987, Kulkarni et al 1995, Orbak et al 2005, Wakeling et al 2010].

Poor oral hygiene in the presence of dental crowding can lead to increased risk for dental caries.

Genitourinary problems have been observed but are uncommon. The most common anomalies are hypospadias and cryptorchidism. Renal anomalies, including hydronephrosis, renal tubular acidosis, posterior urethral valves, and horseshoe kidney have been reported [Arai et al 1988, Ortiz et al 1991].

Neoplasia. Individuals with RSS do not appear to have a significantly increased incidence of neoplasia despite occasional reports of malignancies, including Wilms tumor, hepatocellular carcinoma, and craniopharyngioma [Draznin et al 1980, Chitayat et al 1988, Bruckheimer & Abrahamov 1993].

Genotype-Phenotype Correlations

Using methylation-sensitive restriction enzymes HpaII or NotI to measure the degree of methylation of H19, Bruce et al [2009] developed a scale of extreme H19 hypomethylation, moderate H19 hypomethylation, normal H19 methylation, and maternal UPD7 (normal H19 methylation). They determined that children with RSS with extreme H19 hypomethylation (i.e., ≤ -6 SD or <9% methylation) were more likely to have more severe skeletal manifestations (including radiohumeral dislocation, syndactyly, greater limb asymmetry, and scoliosis) than children with RSS with moderate hypomethylation and those with maternal UPD7.

A study by Wakeling et al [2010] compared clinical features of children with RSS caused by IC1 methylation defects to those with maternal UPD7. They found considerable overlap in the phenotype: fifth finger clinodactyly and congenital anomalies were more frequent in children with IC1 hypomethylation than in those with maternal UPD7, whereas learning difficulties and speech disorders were more frequent in children with maternal UPD7 than in those with IC1 hypomethylation.

The low risk of malignancy is significant, given that at least some individuals with RSS have mutations in the imprinted region of chromosome 11p15.5 that have been associated with Wilms tumor, hepatoblastoma, and other abdominal tumors in individuals with Beckwith-Wiedemann syndrome. The tumor risk, therefore, appears to be increased with mutations related to overgrowth, as opposed to growth retardation.

Prevalence

The prevalence is estimated to be one in 100,000 [Christoforidis et al 2005].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Russell-Silver syndrome (RSS), the following evaluations are recommended:

• Assessment and plotting of growth curves. For European children, see Wollmann et al [1995]; for North American children, see the MAGIC Foundation.

• Physical examination for evaluation of possible limb-size asymmetry and oral and craniofacial abnormalities

• For most children with RSS, evaluation for growth hormone deficiency by standard methods

• For children with diaphoresis, evaluation for hypoglycemia

• For children suspected of having gastroesophageal reflux disease (GERD), evaluation for esophagitis including barium swallow studies, pH probe, and endoscopy

• Screening assessment of neurocognitive development, language, and muscle tone

Treatment of Manifestations

Growth. Children with any condition associated with body differences and/or short stature are often sensitive about body image. These factors can play a significant role in self-image, peer relationships, and socialization. Thus, psychological counseling is frequently helpful for children with RSS.

Human growth hormone therapy in children with intrauterine growth retardation of all causes has significantly improved growth and final height [Albanese & Stanhope 1997, Azcona et al 1998, Czernichow & Fjellestad-Paulsen 1998, Saenger 2002]. Specifically, children with RSS have benefited from growth hormone supplementation even in the absence of growth hormone deficiency [Albanese & Stanhope 1997], including significant growth acceleration and improved final height [Azcona et al 1998] and continued normal growth rate after the discontinuation of growth hormone therapy [Azcona & Stanhope 1999].

Such treatment is best undertaken in a center with experience in managing growth disorders.

One study demonstrated significant increase in height in children with RSS treated with growth hormone, but without a change in body or limb asymmetry [Rizzo et al 2001].

Children with RSS with UPD7 had more gain in height with growth hormone therapy compared to children with 11p15.5 epimutations possibly because children with 11p15.5 methylation abnormalities showed elevated levels of insulin-like growth factor II (product of IGF2); children with RSS with UPD7 had response characteristics similar to other children who were small for gestational age [Binder et al 2008].

A later study looking at both IGF1 and IGF binding protein-3 (IGFBP-3) levels revealed no correlation between changes in the levels of these proteins and growth velocity after treatment with growth hormone; however, the diagnosis of RSS was based solely on clinical presentation and no data regarding testing for 11p15 methylation defects or maternal UPD7 were reported [Beserra et al 2010].

In a recent long term outcome study of 26 children with RSS treated with growth hormone for a median period of 9.8 years, a significant response was noted with median height of -2.7 SD at the beginning of therapy and a median height of -1.3 SD at the conclusion of therapy [Toumba et al 2010].

Unfortunately it is difficult to interpret the results of many studies of children with RSS who have received growth hormone, given the known genetic heterogeneity of the disorder and lack of etiologic data included in these studies. Also, it will be important to look at the long-term effects of growth hormone therapy on children with RSS, especially with respect to influence on final adult height and any possible changes in orthopedic management for those individuals with limb-length asymmetry.

Growth hormone deficiency. Treatment with human growth hormone is necessary in the presence of documented growth hormone deficiency.

Skeletal abnormalities. Lower-limb length discrepancy exceeding 3 cm can lead to compensatory scoliosis and thus requires intervention. Initial treatment is use of a shoe lift. In older children, distraction osteogenesis or epiphysiodesis can be considered.

Neurodevelopment

• For infants with hypotonia, referral to an early-intervention program and physical therapist

• For children with evidence of delay, referral for early intervention and speech and language therapy

• For school-age children, working with the school system to address learning disabilities through appropriate neuropsychological testing and an individualized educational plan

Hypoglycemia should be treated in a standard manner with dietary supplementation, frequent feedings, and use of complex carbohydrates.

Gastrointestinal disorders should be aggressively managed.

• Treatment of gastroesophageal reflux initially with positioning and thickened feeds is recommended along with use of acid blocking medications (preferably proton pump inhibitors such as omeprazole or patoprazole) as needed. Surgical management with fundoplication may be necessary in more severe cases or in instances in which conservative measures are unsuccessful.

• Feeding aversion can be addressed with therapy by a speech pathologist and/or occupational therapist.

Craniofacial anomalies. For those children with severe micrognathia or cleft palate, management by a multidisciplinary craniofacial team is recommended. Orthognathic surgery is rarely required.

Dental hygiene and dental crowding can be appropriately managed in a routine manner by pediatric dentists and orthodontists.

Genitourinary abnormalities

• Referral of males with cryptorchidism to a urologist; surgery as required

• Referral of males with micropenis to an endocrinologist; androgenic hormone therapy as indicated

Neoplasia. The risk for malignancies in individuals with RSS is low. Although body asymmetry may be present, it appears not to be hemihypertrophy, as seen in Beckwith-Wiedemann syndrome; therefore, routine serial abdominal and renal sonograms are not indicated for children with RSS.

Surveillance

The following are appropriate:

• Monitoring of growth with special attention to growth velocity

• In infancy and in older children with diaphoresis or poor appetite, monitoring of blood glucose concentration for hypoglycemia

• At each well-child visit in early childhood, examination and measurement of limb-length discrepancy

• Close monitoring of speech and language development

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Russell-Silver syndrome (RSS) has multiple etiologies including: loss of paternal methylation at the H19-IGF2 imprinting center 1 (IC1) and maternal uniparental disomy for chromosome 7 (UPD7) (see Testing). Autosomal dominant or autosomal recessive inheritance is rare [Ounap et al 2004].

Risk to Family Members — Chromosome 11p15.5-Related RSS: Loss of Paternal Methylation at H19-IGF2 IC1

Parents of a proband

• When a proband has RSS as the result of an imprinting defect on chromosome 11p15.5, both parents are usually unaffected.

• Bartholdi et al [2009] reported a father and daughter with RSS, both of whom have a methylation defect at H19-IGF2 IC1.

• Germline mosaicism is presumed to be present in the unaffected fathers in two families in which epigenetic mutations were identified in sibs [Bartholdi et al 2009].

Sibs of a proband

• When a proband has RSS as the result of an imprinting defect on chromosome 11p15.5, the risk to the sibs is usually not increased over that of the general population.

• Father-to-child transmission of the imprinting defect on chromosome 11p15.5 and presumed germline mosaicism in unaffected fathers have been reported; thus, the risk to sibs may be increased in some families.

Offspring of a proband

• The risk to offspring is probably low.

• With the exception of one report of father-to-daughter transmission of the imprinting defect on chromosome 11p15.5 [Bartholdi et al 2009], no data to determine recurrence risks for probands with an imprinting defect on chromosome 11p15.5 are available.

Other family members of a proband. When a proband has RSS as the result of an imprinting defect on chromosome 11p15.5, the risk to other family members is likely not increased over that of the general population.

Risk to Family Members — Chromosome 7-Related RSS: Maternal Uniparental Disomy 7

Parents of a proband. When a proband has RSS as the result of maternal UPD7, both parents are predicted to be unaffected.

Sibs of a proband. When a proband has RSS as the result of maternal UPD7, the risk to the sibs is not increased over that of the general population.

Offspring of a proband. The risk to offspring is probably low. No data to determine recurrence risks for probands with maternal UPD7 are available.

Other family members of a proband. When a proband has RSS as the result of maternal UPD7, the risk to other family members is not increased over that of the general population.

Related Genetic Counseling Issues

Empiric risk. In the 45%-60% of individuals with an identified 11p15 hypomethylation or maternal UPD7 whose parents and sibs have normal stature, the risk for recurrence for sibs is not increased and is the same as for the general population.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Because most occurrences of RSS are in a single family member only, most pregnancies are not identified to be at increased risk for the disorder. Therefore, prenatal diagnosis for RSS is usually not possible.

For pregnancies in which intrauterine growth retardation is identified by fetal ultrasonography, prenatal testing can be made available for loss of paternal methylation at the H19-IGF2 IC1 and maternal UPD7, utilizing PCR molecular testing of the parents and fetal cells obtained by amniocentesis. Note: intrauterine growth retardation often cannot be satisfactorily identified until the third trimester.

Molecular Genetic Pathogenesis

Chromosome 11p15.5-related RSS. The importance of imprinted genes at chromosome 11p15.5 for fetal growth is known [DeChiara et al 1990, Fitzpatrick et al 2002, Eggermann 2009]. RSS is caused by epigenetic alterations at imprinted domain 1 [Gicquel et al 2005] (Figure 1), while the overgrowth disorder Beckwith-Wiedemann syndrome results from epigenetic alterations at both imprinted domains 1 and 2 (for comparison see Beckwith-Wiedemann Syndrome - Figure 1). The mechanism whereby differentially methylated domains at 11p15.5 affect gene transcription is not clearly understood. One model proposes that imprinting center 1 (IC1) binding of the zinc-finger CTCF protein controls chromatin conformation, which leads to activation or inactivation of chromatin domains [Li et al 2008, Demars et al 2010]. For RSS, domain 1 hypomethylation-induced changes in chromatin structure block transcriptional signals from cis enhancer sequences and/or from regulatory proteins, thus turning off IGF2 and allowing biallelic expression of H19. Studies related to H19-IGF2 and IC1 as causal in RSS include Obermann et al [2004], Gicquel et al [2005], Schönherr et al [2007], and Turner et al [2010].

• H19 is an imprinted maternally expressed transcript (non-protein coding) RNA of 2322 nucleotides. Imprinting of H19 is regulated by IC1 domain (Figure 1).

• IGF2 is an imprinted paternally expressed transcript that encodes a member of the insulin family of polypeptide growth factors that is involved in development and growth. NM_000612.4, the most predominant transcript, encodes the 180-amino acid insulin-like growth factor II isoform 1 (NP_000603.1).

Chromosome 7-related RSS. The specific genetic loci responsible for UPD7 imprinting have not yet been identified; however, given the cases reported with maternal UPD of the long arm of chromosome 7 (7q), it is likely that the genes of interest are on 7q [Eggermann 2008]. Hannula et al [2001] reported a patient with maternal UPD of 7q31-qter.

Published Guidelines/Consensus Statements

1. American College of Medical Genetics Statement on diagnostic testing for uniparental disomy (pdf). 2001. Available at www.acmg.net. Accessed 5-27-11.

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Suggested Reading

1. Abu-Amero S, Wakelin EL, Preece M, Whittaker J, Stanier P, Moore GE. Epigenetic signatures of Silver-Russell syndrome. J Med Genet. 2010;47(3):150–4. [PubMed: 20305090]
2. Bruce S, Hannula-Jouppi K, Pouskari M, Fransson I. Submicroscopic genomic alterations in Silver-Russell syndrome and Silver-Russell-like patients. J Med Genet. 2010;47:356–60. [PubMed: 19762329]
3. Hall JG. Review and hypothesis: syndromes with severe intrauterine growth restriction and very short stature—are they related to the epigenetic mechanism(s) of fetal survival involved in the developmental origins of adult health and disease? Am J Med Genet Part A. 2010;152A:512–27. [PubMed: 20101705]
4. Rossignol S, Netchine I, Le Bouc Y. Epigenetics in Silver-Russell syndrome. Best Practice & Research Clinical Endocrinology & Metabolism. 2008;22(3):403–14. [PubMed: 18538282]
5. Schönherr N, Jäger S, Ranke MB, Wolmann HA, Binder G, Eggermann T. No evidence for isolated imprinting mutations in the PEG1/MEST locus in Silver-Russell patients. Eur J Med Genet. 2008;51:322–4. [PubMed: 18585117]

Revision History

• 2 June 2011 (me) Comprehensive update posted live

• 9 March 2007 (hs) Revision: methylation analysis for H19 clinically available

• 7 September 2006 (me) Comprehensive update posted to live Web site

• 5 March 2004 (me) Comprehensive update posted to live Web site

• 2 November 2001 (me) Review posted to live Web site

• February 2001 (hs) Original submission