Broad clinical spectrum in Silver-Russell syndrome and consequences for genetic testing in growth retardation

Abstract

Objective: Silver-Russell syndrome is a heterogenous disorder characterized by severe intrauterine growth restriction, lack of catch-up after birth, and specific dysmorphisms. In approximately 10% of patients, maternal uniparental disomy of chromosome 7 is detectable, but hypomethylation of the imprinting in 11p15 is the major epigenetic disturbance in Silver-Russell syndrome. The use of strict clinical criteria, indeed, results in relatively high detection rates for the 11p15 epimutation, but we feel that the application of a strict clinical scoring system is not useful in clinical workaday life because of the broad clinical spectrum in 11p15 epimutation and maternal uniparental disomy of chromosome 7 carriers.

Patients and methods: We report on our experience of molecular testing in 188 patients referred for routine diagnostics of Silver-Russell syndrome and in a group of 20 patients with isolated intrauterine growth restriction/postnatal growth retardation.

Results: The molecular genetic results in both groups of data showed that 11p15 epimutation and maternal uniparental disomy of chromosome 7 carriers did not always show the unambiguous Silver-Russell syndrome phenotype.

Conclusions: In addition to patients with the classical Silver-Russell syndrome phenotype fulfilling the Silver-Russell syndrome-specific scores, genetic testing for the 11p15 epimutation and/or maternal uniparental disomy of chromosome 7 should also be considered in case of "Silver-Russell syndrome-like" phenotypes, for example, mild intrauterine growth restriction and postnatal growth retardation associated with a prominent forehead and triangular face or asymmetry as the only clinical signs. In particular, the lack of intrauterine growth restriction in patients with a Silver-Russell syndrome-like phenotype should not automatically result in exclusion from molecular testing.