What causes Silver-Russell syndrome (SRS)?

Updated: Feb 11, 2019
  • Author: Sunil Kumar Sinha, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Silver-Russell syndrome is both clinically and genetically a heterogeneous disorder, and the basic underlying defect is not known. Silver-Russell syndrome usually occurs sporadically and its etiology is not identified in most cases. To date, genetic and epigenetic alteration can be detected in only half of cases with typical features. Various molecular defects have been reported, mostly involving chromosomes 7 and 11. Defects have also been reported in chromosomes 1, 15, 17 and X. A few cases of autosomal dominant transmission have been described, including ring 2 chromosome, balanced translocation of band 17q25, and duplication of band 7p11.2-p13.

Approximately 10% of patients have proven uniparental disomy (UPD) and abnormal methylation. Imprinting may play a role in the clinical phenotype of Silver-Russell syndrome in these patients. UPD results from inheritance of both alleles from one parent and no allele from the other parent (ie, loss of the allele contributed by one of the parents). Multiple reports suggest that approximately 10% of patients may have maternal UPD of chromosome 7 (mUPD7). Heterodisomy (inheritance of both alleles from one parent) and isodisomy (inheritance of 2 copies of a single allele from one parent) are both demonstrated. Partial heterodisomy or isodisomy have also been shown. Findings also suggest that imprinting defects on chromosome 11 within the 11p15 region may also play a role in Silver-Russell syndrome. [10]

Imprinting involves the methylation of particular bases within an allele. The methylation pattern differs depending on whether the allele is obtained from the mother or from the father's genome. If the allele is methylated, then that gene selectively is turned off.

Assisted reproductive technologies (ARTs) may increase the risk of imprinting disorders such as Silver-Russell syndrome. [11]  A study by Hattori et al found the frequency of Silver-Russell syndrome to be 8.91-fold greater in association with ART. [12] The investigators also determined that DNA methylation variations were more numerous and widespread in Silver-Russell syndrome patients conceived through ART than in those who were spontaneously conceived. A literature review by Cortessis et al indicated that the summary odds ratio for the development of Silver-Russell syndrome in the context of ART is 11.3. [13]

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