Beckwith-Wiedemann Syndrome (BWS)/Russell-Silver Syndrome (RSS) Molecular Analysis
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Beckwith-Wiedemann syndrome (BWS) is a disorder characterized by prenatal and/or postnatal overgrowth, neonatal hypoglycemia, congenital malformations, and an increased risk for embryonal tumors. Physical findings are variable and can include abdominal wall defects, macroglossia, and hemihyperplasia. The predisposition for tumor development is associated with specific tumor types such as adrenal carcinoma, nephroblastoma (Wilms tumor), hepatoblastoma, and rhabdomyosarcoma. In infancy, BWS has a mortality rate of approximately 20%.
Current data suggest that the etiology of BWS is due to dysregulation of imprinted genes in the 11p15 region of chromosome 11, including H19 (maternally expressed), LIT1 (official symbol KCNQ1OT1; paternally expressed), IGF2 (paternally expressed), and CDKN1C (aliases p57 and KIP2; maternally expressed). Expression of these genes is controlled by 2 imprinting centers (IC).
Approximately 85% of BWS cases appear to be sporadic, while 15% of cases are associated with an autosomal dominant inheritance pattern. When a family history is present, the etiology is often due to inherited point mutations in CDKN1C or an unknown cause. The etiology of sporadic cases includes:
-Hypomethylation of imprinting center 2 (IC2) (LIT1): approximately 50% to 60%
-Paternal uniparental disomy of chromosome 11: approximately 10% to 20%
-Hypermethylation of imprinting center 1 (IC1) (H19): approximately 2% to 7%
-Unknown: approximately 10% to 20%
-Point mutation in CDKN1C: approximately 5% to 10%
-Cytogenetic abnormality: approximately 1% to 2%
-Differentially methylated region 1 (DMR1) or DMR2 microdeletion: rare
The clinical presentation of BWS is dependent on which gene in the 11p15 region is involved. The risk for cancer has been shown to be significantly higher in patients with abnormal methylation of IC1 (H19) versus IC2 (LIT1). In patients with abnormal methylation of IC2 (LIT1), abdominal wall defects and overgrowth are seen at a higher frequency.
Russell-Silver syndrome (RSS) is a rare genetic condition with an incidence of approximately 1 in 100,000. RSS is characterized by pre- and postnatal growth retardation with normal head circumference, characteristic facies, fifth finger clinodactyly, and asymmetry of the face, body, and/or limbs. Less commonly observed clinical features include cafe au lait spots, genitourinary anomalies, motor, speech, cognitive delays, and hypoglycemia. Although clinical diagnostic criteria have been developed, it has been demonstrated that many patients with molecularly confirmed RSS do not meet strict clinical diagnostic criteria for RSS. Therefore, most groups recommend a relatively low threshold for considering molecular testing in suspected cases of RSS.
RSS is a genetically heterogeneous condition that is associated with genetic and epigenetic alterations at chromosome 7 and the chromosome 11p15.5 region. The majority of cases of RSS are sporadic, although familial cases have been reported. The etiology of sporadic cases of RSS includes:
-Hypomethylation of IC1 (H19): approximately 30% to 50%
-Maternal uniparental disomy (UPD) of chromosome 7: approximately 5% to 10%*
-11p15.5 duplications: rare
-Chromosome 7 duplications: rare
*Note that this test does not detect chromosome 7 UPD. However, testing is available. See UPD/82970 Uniparental Disomy.
The clinical phenotype of RSS has been associated with the specific underlying molecular etiology. Patients with hypomethylation of IC1 (H19) are more likely to exhibit "classic" RSS phenotype (ie, severe intrauterine growth retardation, postnatal growth retardation, and asymmetry), while patients with maternal UPD7 often show a milder clinical phenotype. Despite these general genotype-phenotype correlations, many exceptions have been reported.
Methylation abnormalities of IC1 (H19) and IC2 (LIT1) can be detected by methylation-sensitive multiple ligation-dependent probe amplification. While testing can determine methylation status, it does not identify the mechanism responsible for the methylation defect (such as paternal uniparental disomy or cytogenetic abnormalities). Hypomethylation of IC2 (LIT1) is hypothesized to silence the expression of a number of maternally expressed genes, including CDKN1C. Hypermethylation of IC1 is hypothesized to silence the expression of H19, while also resulting in overexpression of IGF2. Absence of CDKN1C and H19 expression, in addition to overexpression of IGF2, is postulated to contribute to the clinical phenotype of BWS. Hypomethylation of IC1 is hypothesized to result in overexpression of H19 and underexpression of the IGF2, which is thought to contribute to the clinical phenotype of RSS.
Confirming a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS) or Russell-Silver syndrome (RSS)
Prenatal diagnosis if there is a high suspicion of BWS/RSS based on ultrasound findings or in families at risk for BWS/RSS
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
In addition to disease-related probes, the multiple ligation-dependent probe amplification technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
Methylation status cannot be assessed on chorionic villus specimens.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories at 800-533-1710 or 507-266-5700 for instructions for testing patients who have received a bone marrow transplant.
This assay does not detect maternal uniparental disomy of chromosome 7 or cytogenetic abnormalities such as translocations, inversions, or duplications.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. DeBaun MR, Niemitz EL, McNeil DE, et al: Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann Syndrome with cancer and birth defects. HumGenet 2002;70:604-611
2. Choufani S, Shuman C, Weksberg R: Beckwith-Wiedemann Syndrome. Am J of Med Genet 2010;154C:343-354
3. Wakeling EL: Silver-Russell syndrome. Arch Dis Child 2011;96(12):1156-1161
4. Eggermann T, Begemann M, Binder G, et al: Silver-Russell syndrome: genetic basis and molecular genetic testing. Orphanet J Rare Dis 2010;5:19-26
5. Priolo M, Sparago A, Mammi C, et al: MS-MLPA is a specific and sensitive technique for detecting all chromosome 11p15.5 imprinting defects of BWS and SRS in a single-tube experiment. Euro J of Hum Genet 2008;16:565-571