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Russell-Silver Syndrome

Silver-Russell Syndrome

Silver-Russell syndrome (SRS) or Russell-Silver syndrome (RSS) is a  rare genetic disorder that is presented in children with a small triangular face, low birth weight, slow growth (dwarfism), and limb asymmetry. It was originally described in 1953 by Silver and colleagues and later by Russell in 1954. Genomic aberration in maternal genes has been identified as one of the causes.


Presentation

RSS affected patient is short in stature. Decrease in total body cell mass occurs as a result of intrauterine growth retardation. Though the child grows normally after birth, it always remains smaller than the contemporaries. Some studies have shown insufficient growth hormone secretion as one of the contributory factors [6]. Clinical and physical features vary among affected persons. These include craniofacial disproportion (triangular faces), asymmetric limb, curling up of the fifth digit (small finder or pinky) called clinodactyly, campodactyly (fixed flexion of digits), syndactyly, term gestation, low set ears, normal intelligence, low birth weight and downward curvature of the corners of the mouth. The classic features of RSS are normal head circumference looking out of proportion with a small body, blue sclera and high forehead, micrognathia, prominent nasal bridge, high forehead tapering to a small jaw, down-turning corners of the mouth and micrognathia.  

Newborns show two or more standard deviation (SD) below the mean birth weight, whereas, the postnatal growth is two or more SD below the mean for length or height. The growth rate is normal in RSS. However, during first three years of life the growth rate is slow, and henceforth becomes parallel, but below the curve of the third percentile [7]. Limb asymmetry in RSS is due to hemihypotrophy, with diminished growth of the affected side. An average male adult height is 151.2 cm and that of an adult female is 139.9 cm. There are evidences to show significant risk for delay in development and learning abilities.

Fishing
  • Fluorescence in situ hybridization (FISH) mapping revealed that the breakpoints on 7p14 were localized to the same novel gene, C7orf10, which encompasses 700 kb of DNA.[ncbi.nlm.nih.gov]
  • View Article PubMed Google Scholar Mergenthaler S, Sharp A, Ranke MB, Kalscheuer VM, Wollmann HA, Eggermann T: Gene dosage analysis in Silver-Russell syndrome: use of quantitative competitive PCR and dual-color FISH to estimate the frequency of duplications[doi.org]
Cafe-Au-Lait Spots
  • Russell-Silver dwarfism Pediatrics An idiopathic and sporadic condition characterized by extremely short stature and body and facial asymmetry, excessive sweating, a small triangular face which makes the skull look large by comparison, inward curved fingers, cafe-au-lait[medical-dictionary.thefreedictionary.com]
  • Thin lips [ more ] 0000233 Upper limb asymmetry Unequal size of arms 0100560 5%-29% of people have these symptoms Abnormal vagina morphology 0000142 Abnormality of the cardiovascular system Cardiovascular abnormality 0001626 Autistic behavior 0000729 Cafe-au-lait[rarediseases.info.nih.gov]
  • Less commonly observed clinical features include cafe au lait spots, genitourinary anomalies, motor, speech, cognitive delays, and hypoglycemia.[mayomedicallaboratories.com]
Skin Lesion
  • Russell-Silver syndrome is characterized by asymmetric intrauterine growth retardation, postnatal failure to thrive, distinct facial features, limb asymmetry, excessive sweating and minor skin lesions.[ncbi.nlm.nih.gov]
Cutaneous Manifestation
  • We present the first instances of a large, unilateral, achromic patch as an additional cutaneous manifestation of the Russell-Silver syndrome.[ncbi.nlm.nih.gov]
Skeletal Dysplasia
  • A new skeletal dysplasia syndrome with rhizomelia of the humeri and other malformations. Clin Genet. 1986 Jan; 29 (1):83–87. [ PubMed ] [ Google Scholar ] Adeyokunnu AA.[ncbi.nlm.nih.gov]
  • dysplasia MVRCS association Nail-patella syndrome Nance-Horan syndrome Neu-Laxova syndrome Neurocutaneous syndrome Nodular embryo Noonan syndrome Noonan's syndrome Oculo-cerebro-cutaneous syndrome Oculodentodigital syndrome Oculodento-osseous dysplasia[icd9data.com]
  • Disproportionate short stature is suggestive of skeletal dysplasia. Photosensitive skin rash or recurrent bronchopulmonary infections should prompt investigation for chromosome breakage disorders.[doi.org]
Thigh Pain
  • Both presented with groin or thigh pain in their shortened side together with a progressive limp. They were treated conservatively, and when reviewed 6 1/2 years after diagnosis the lesions of the hip had improved clinically and radiographically.[ncbi.nlm.nih.gov]
Small, Triangular Face
  • INTRODUCTION: Russell-Silver Syndrome (RSS) is a genetically determined condition characterized by severe intrauterine and postnatal growth retardation; relative macrocephaly; a small, triangular face; and fifth-finger clinodactyly.[ncbi.nlm.nih.gov]
  • The wide prominent forehead contrasts with the small, triangular face with a small pointed chin, a wide mouth with thin lips and down-turned corners, large eyes and bluish sclera.[orpha.net]
  • Russell-Silver dwarfism, Russell-Silver syndrome Russell-Silver syndrome Russell-Silver dwarfism Pediatrics An idiopathic and sporadic condition characterized by extremely short stature and body and facial asymmetry, excessive sweating, a small triangular[medical-dictionary.thefreedictionary.com]
  • triangular face Distinctive facial features Prominent forehead Narrow chin Small jaw Downturned corners of the mouth Fifth finger clinodactyly May have coffee coloured birthmark *Please be aware, not all of the characteristics may be present* Other information[littlepeopleuk.org]
Downturned Corners of the Mouth
  • corners of the mouth Fifth finger clinodactyly May have coffee coloured birthmark *Please be aware, not all of the characteristics may be present* Other information about Russell-Silver Syndrome Affects men and women equally Life expectancy is not affected[littlepeopleuk.org]
  • corners of mouth Downturned corners of the mouth Downturned mouth [ more ] 0002714 Failure to thrive in infancy Faltering weight in infancy Weight faltering in infancy [ more ] 0001531 Gastroesophageal reflux Acid reflux Acid reflux disease Heartburn[rarediseases.info.nih.gov]
  • Many children with Russell-Silver syndrome have a small, triangular face with distinctive facial features including a prominent forehead , a narrow chin , a small jaw , and downturned corners of the mouth .[ghr.nlm.nih.gov]
  • corners of the mouth 46% 50% (n 22) 55% (n 9) 57.3% micrognathia 73% (n 15) 55% (n 9) 44% ear anomalies 53% 78.6% (n 14) 40.3% teeth anomalies 28% 64% (n 14) 0% (n 7) 28% The frequency of SRS is currently unknown, but it is probably underdiagnosed due[doi.org]
Cryptorchidism
  • […] anomalies Diagnosis [ edit ] Minimal diagnostic criteria includes IUGR Postnatal growth retardation Normal head circumference Triangular face Fifth finger clinodactyly Normal psychomotor development Supportive criteria Short arm length Limb length asymmetry Cryptorchidism[en.wikibooks.org]
  • […] facial shape [ more ] 0000325 30%-79% of people have these symptoms Abnormality of the calcaneus Abnormal heel bone 0008364 Arthralgia Joint pain 0002829 Clinodactyly of the 5th finger Permanent curving of the pinkie finger 0004209 Constipation 0002019 Cryptorchidism[rarediseases.info.nih.gov]
  • Cryptorchidism can sometimes resolve spontaneously, although some boys require surgical treatment. Hypospadias requires surgery, ideally by an experienced pediatric surgeon. Kidney (renal) abnormalities are treated along standard guidelines.[rarediseases.org]
  • Cryptorchidism requiring orchiopexy should be referred for proper hormonal and surgical management. Micropenis in males should be managed by endocrinologists and hormone therapy with androgens may be indicated.[symptoma.com]
  • […] crowded teeth · low-set, posteriorly rotated &/or prominent ears · unusually, high-pitched voice in early years · clinodactly (inward curving) of the 5th finger · syndactyly (webbing) of the 2nd and 3rd toes · hypospadius - abnormal opening of the penis · cryptorchidism[coltongeorge.com]

Workup

Karyotyping and chromosomal microarrays are done to identify Russell-Silver syndrome from various other genetic disorders. Blood samples from both patients and parents are analyzed by polymerase chain reaction (PCR) for the presence ofhypomethylation at chromosome 11p15 and uniparental disomy of chromosome 7. 
A hand radiograph is used to determine bone age. The following findings are seen in a plain hand film:

  • Delayed bone age 
  • Middle phalanx of the fifth finger is unusually small (80% of RSS patients)
  • Distal phalanges with ivory epiphyses 
  • Base of second metacarpal with pseudo epiphyses

The initial diagnosis of RSS requires a thorough clinical assessment of the child along with a detailed family history and identification of specific characteristic features, especially normal head circumference in children with growth retardation both before and after birth. Diagnosis of RSS is difficult to make because of the existence of varied phenotypes. Prenatal ultrasound is helpful in identifying intrauterine growth retardation. There is no specific phenotype of RSS since it is genetically heterogeneous. Therefore, while making diagnosis one should look for features that are unique to RSS.

Delayed Bone Age
  • However, in each child with RSS, a particular attention should be given to a decreased height velocity, a severely delayed bone age as well as a history of major perinatal problems.[ncbi.nlm.nih.gov]
  • bone age Low birth weight Short height, short arms, stubby fingers and toes Stomach and intestine problems such as acid reflux and constipation The condition is usually diagnosed by early childhood.[nlm.nih.gov]
  • X-ray abnormalities include: Delayed bone age. 'Ivory' epiphyses of distal phalanges. Small middle phalanx of the little finger - present in 4 out of 5 cases. Pseudo-epiphyses at the base of second metacarpal.[patient.info]
  • Symptoms Symptoms can include: Birthmarks that are the color of coffee with milk ( cafe-au-lait marks) Curving of the pinky toward the ring finger Delayed bone age Failure to thrive Gastroesophageal reflux disease Kidney problems, such as: Horseshoe kidney[coordinatedhealth.com]

Treatment

Although RSS originates with antenatal growth retardation, the treatment strategy focuses mainly on postnatal intervention procedures. Growth hormone therapy is recommended in RSS-affected child who do not show adequate growth development by 2 years of age. Growth hormone (GH) supplementation in the absence of growth hormone deficiency has been found to be beneficial in children with RSS [8], resulting in significant improvement in growth and achievement of final height [9]. The normal growth rate is maintained even after growth hormone therapy is stopped [10]. GH therapy started in GH deficient children diagnosed later in life was likewise successful [11]. Recombinant human growth hormone (rhGH) has shown satisfactory improvement in height of RSS patients. However, further studies are needed to be done to establish the appropriate dosage schedule that can benefit adult patients.

For patients with feeding difficulties percutaneous endoscopic gastrostomy (PEG) or nasogastric feeds should be started for the growth and maintenance. Gastroesophageal reflux can be initially alleviated with proper positioning, thickening of feeds and acid-blocking medications (e.g. proton pump inhibitors or ranitidine). Otherwise, surgical intervention with fundoplication may be required.

Braces and oral surgery can be used to treat dental abnormalities. Language and speech therapy may be required by affected children with speech difficulties, especially those with genetic deficiency involving matUPD7. An audiological examination can help to rule out hearing loss as a cause of speech problems. Lower-limb asymmetry exceeding 3 cm in length needs to be corrected. Alternatively, in older children, distraction osteogenesis or epiphysiodesis is recommended. In individuals with difficulties in walking due to limb asymmetry need special braces and shoes to help maintain balance and gait. Surgical intervention may be done, but only after growth has ceased.

There are established guidelines in the management of RSS. Prompt diagnosis and treatment can ensure that patients can achieve their highest possible potential for growth and development. Malnutrition and low blood sugar levels can be avoided through proper and adequate nutrition. Hypoglycemia can be treated according to standard practices, including frequent feeding, dietary supplements and using complex carbohydrates such as corn starch. A multidisciplinary team of craniofacial experts should be consulted for cleft palate or severe micrognathiaCryptorchidism requiring orchiopexy should be referred for proper hormonal and surgical management. Micropenis in males should be managed by endocrinologists and hormone therapy with androgens may be indicated. Hypospadias require corrective surgery and should be done by an experienced pediatric surgeon.

Prognosis

Prognosis of RSS is good, though learning disability is seen in some patients. Early milestones may show some delay due to the decrease in muscle bulk and relatively large head, but normal intelligence is usually preserved in this syndrome. Prompt recognition of these early manifestations is essential for timely intervention. Early detection helps in prompt administration of general and orthodontic corrective measures to ensure good physical and psychological development of the child.

Etiology

Russell-Silver syndrome is sporadic in distribution and its etiology is still not clearly understood. However, the majority of cases show two types of genetic variations. These are: 1) maternal disomy of chromosome 7, that is, inheritance of 2 copies of the same chromosome from the mother instead of one each from the mother and father as in a normal zygote and 2) abnormalities in the chromosome 11p15 imprinting region. Most of the patients show hypomethylation in chromosome 11p15 imprinting center 1 (IC1) [1] [2] [3]. Maternal uniparental disomy (UPD) of chromosome 7 is found in 7-10% of RSS cases. Varying molecular defects have also been detected in chromosomes 1, 15, 17 and X.

Various defects have also been seen on chromosome 7 and chromosome 11. No obvious cause can be linked with the disorder for most patients. At present, genetic and epigenetic aberrations can be found in half of cases showing typical RSS features. Autosomal dominant transmission has been seen in a few cases and includes ring 2 chromosome aberration, balanced translocation of band 17q25, and duplication of band 7p11.2-p13.

Epidemiology

Russell-Silver Syndrome has been diagnosed in patients without a family history of the disease. The overall incidence rate varies from 1:3,000 to 1:100,000, regardless of age or race. Some researchers claim that the incidence rate may vary from 1 in 75,000-100,000. So far, more than 500 cases have been found worldwide, with both male and female affected equally [4] [5].
Asymmetry of limbs has been seen in 60% of the patients. Clinical manifestations are more apparent in infants and younger children with small triangular faces being an important finding. In the past, infants with intrauterine growth retardation and normal head circumference were incorrectly diagnosed to have RSS. The exact frequency of the disorder is difficult to determine as many cases go unrecognized, undiagnosed or misdiagnosed.

Sex distribution
Age distribution

Pathophysiology

Studies have shown that changes in methylation, a process by which methyl groups are attached to certain portions of DNA are responsible for abnormalities in RSS. Methylation facilitates imprinting of the gene's parent of origin during the formation of the egg and sperm cells. Disruption of methylation in RSS involves the H19 and IGF2 genes, located adjacent to each other on chromosome 11. Since these genes determine normal growth, loss of methylation abolishes the regulation of these genes, causing slow growth and other manifestations of the disorder. This accounts for around one third of all cases of RSS. Whereas paternal genes enhance growth, maternal genes restrain growth.

Both structural changes in a particular gene (genetics) and changes in its function or expression (epigenetics) account for the abnormalities associated with RSS. Epigenetics entails chromatin modifications and not changes in the DNA sequence per se. These are essential for development in terms of the differentiation of cell types, for X-chromosome inactivation and genomic imprinting as well. Alterations in the methylation of certain cluster of genes result in differentially methylated regions (DMR′s) or imprinting control regions (ICR′s). Imprinted genes determine the presence or absence of synchronized regulation of gene expression which influence fetal and placental growth.

It has been shown that imprinting errors in RSS are located on chromosomes 7 and 11p15. The clinical manifestations of RSS are linked to generic printing errors. However, the clinical features of RSS are less prominent in older children and adults than in infants and young children. Insufficiency in growth hormone is involved. A significant number of patients have shown deficiency in spurt of growth hormone (GH) secretion along with below normal response to provocative growth hormone stimulation test. 35%-50% of patients with RSS shows hypomethylation of the paternal imprinting center 1 (IC1) of chromosome 11p15.5, whereas, maternal uniparental disomy for chromosome 7 (UPD7) is found in about 10% of the cases.

Prevention

With only a single isolated case seen in families, risk of RSS is usually not considered in most pregnancies. Hence, prenatal diagnosis for RSS is usually not possible. Ultrasonography can identify intrauterine growth retardation in pregnancies and further testing can be done to detect the absence of paternal methylation at the H19-IGF2 IC1 and maternal UPD7.

Summary

Silver-Russell syndrome (RSS) is a rare, hereditary disorder characterized by growth retardation in both intrauterine and postnatal period. It shows a wide range of phenotypic features which vary both in the incidence and individual presentation. One of the common features include a prominent forehead with tapering chin and jaw, giving the appearance of a triangular face. The circumference of the head is normal, but looks out of proportion to small body size. Birth weight of the affected infant and postnatal development of length or height shows two or more SD below the mean. Most RSS pediatric patients exhibit normal intelligence, though they usually show some motor and speech (learning) delays.

Diagnosis of RSS is based mainly on clinical assessment as no specific test or definitive diagnostic criteria is presently available. Confirmatory tests include fetal ultrasonography, polymerase chain reaction, and karyotyping. The genetic defects have been traced to maternal uniparental disomy (UPD) in chromosome 7. Intervention at an early stage is critical. Early recognition of RSS by intrauterine growth retardation during pregnancy helps to ensure timely intervention and prevent long term effects. Treatment is aimed at symptomatic management, growth hormone therapy, measures to improve learning abilities and psychological support.

Patient Information

Russell-Silver syndrome (RSS) is a congenital birth defect that manifests as growth retardation both before and after birth, subnormal weight and height, asymmetry of limbs, triangular face that tapers at the jaw and other abnormalities. The clinical presentation and genetic origin of RSS are varied, hence, there is no one common or unique feature of RSS. Cases of Russell-Silver syndrome are mostly sporadic, that is, the disorder may appear in people with no known history of the disease in the family. Treatment is usually supportive and symptomatic and is focused towards specific symptoms that are present in the patient. There are established guidelines to follow for effective therapy.

Early recognition of the disorder is essential to facilitate the timely application of appropriate treatment measures and to enable the affected individuals to attain their highest possible potential for a normal life. Genetic counseling is recommended for affected individuals and their families to minimize their apprehension.

References

Article

  1. Eggermann T, Spengler S, Gogiel M, Begemann M, Elbracht M. Epigenetic and genetic diagnosis of Silver-Russell syndrome. Expert Rev Mol Diagn. 2012 Jun; 12(5):459-71.
  2. Chiesa N, De Crescenzo A, Mishra K, Perone L, Carella M, Palumbo O, et al. The KCNQ1OT1 imprinting control region and non-coding RNA: new properties derived from the study of Beckwith-Wiedemann syndrome and Silver-Russell syndrome cases. Hum Mol Genet. 2012 Jan 1; 21(1):10-25.
  3. Fuke T, Mizuno S, Nagai T, Hasegawa T, Horikawa R, Miyoshi Y, et al. Molecular and clinical studies in 138 Japanese patients with Silver-Russell syndrome. PLoS One; 2013. 8(3):e60105.
  4. Saal HM, Pagon RA, Pepin MG. Reevaluation of Russell-Silver syndrome. J Pediatr. 1985 Nov;107(5):733-7.
  5. Kumar S, Jain A, Agrawal S, Chandran S. Silver-Russell syndrome: a case report. Cases J. 2008 Nov 9;1(1):304. doi: 10.1186/1757-1626-1-304.
  6. Eggermann T, Gonzalez D, Spengler S, Arslan-Kirchner M, Binder G, Schönherr N. Broad clinical spectrum in Silver-Russell syndrome and consequences for genetic
    testing in growth retardation. Pediatrics. 2009 May;123(5):e929-31. 
  7. Beserra IC, Ribeiro MG, Collett-Solberg PF, Vaisman M, Guimarães MM. IGF-I and IGF Binding Protein-3 Generation Tests and Response to Growth Hormone in Children with Silver-Russell Syndrome. Int J Pediatr Endocrinol. 2010;2010:546854. 
  8. Stanhope R, Albanese A, Azcona C. Children with intrauterine growth retardation: 7-year results. Horm Res. 1997;48(4):173-7.
  9. Azcona C, Albanese A, Bareille P, Stanhope R. Growth hormone treatment in growth hormone-sufficient and -insufficient children with intrauterine growth retardation/Russell-Silver syndrome. Horm Res. 1998;50(1):22-7.
  10. Azcona C, Stanhope R. Absence of catch-down growth in Russell-Silver syndrome after short-term growth hormone treatment. Horm Res. 1999;51(1):47-9.
  11. Gertner JM, Tamborlane WV, Gianfredi SP, Genel M. Renewed catch-up growth with increased replacement doses of human growth hormone. J Pediatr. 1987 Mar;110(3):425-8.

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Last updated: 2018-06-21 23:26