Diagnostic proceeding in Silver-Russell syndrome

Silver-Russell syndrome (SRS) describes a uniform malformation syndrome characterized by pre- and postnatal growth restriction (<3rd percentile) and a typical craniofacial gestalt. The basic defect of SRS is currently unknown, and the number of meaningful genetic tests available is therefore limited. Different chromosomal aberrations have been identified, including in the chromosomal region 7p12-p14. Detailed analyses of numerous candidate genes have not revealed any relevant insights with respect to the etiology of the disease.However, maternal uniparental disomy (UPD) of chromosome 7 (matUPD7), the inheritance of both homologues of chromosome 7 only from the mother, is observed in approximately 10% of SRS patients. Here, we report on our experiences of UPD testing in patients referred to our laboratory with the clinical diagnosis of SRS. A diagnostic algorithm for SRS is suggested.

Eighty-six patients with the clinical diagnosis of SRS were screened for matUPD7 by microsatellite typing. In 13 cases, the clinical data were consistent with the diagnosis of SRS. The other 73 patients were referred for UPD testing with the suspected diagnosis of SRS, but clinical data were scarce.

In total, we identified three new cases of matUPD7: one patient belonged to the cohort of 13 clinically characterized patients; the other two patients were referred with the suspected diagnosis of SRS but initially without detailed reports. DNA studies revealed uniparental heterodisomy 7 in two patients, while the results in the third case were consistent with uniparental isodisomy.

MatUPD7 is predominantly detectable in patients showing SRS features, and testing should therefore be restricted to this group of growth-restricted patients. Generally, a combination of cytogenetic and molecular genetic tests can be offered in SRS, aiming at the detection of chromosomal rearrangements and matUPD7 in >10% of SRS patients.