Silver-Russell Syndrome in 2025: Is It Still a Distinct Diagnostic Entity? (Équipe Netchine)

J Clin Endocrinol Metab. 2025 Jan 2:dgae902.doi: 10.1210/clinem/dgae902

In their recent study, Vimercati et al highlight how next-generation sequencing (NGS) is improving the molecular diagnostic yield in patients with Silver-Russell Syndrome (SRS) suspicion (1). However, are all the genetic variants identified by NGS truly causative of SRS, or could some be linked to differential diagnoses? Moreover, given the molecular heterogeneity identified in this population, is SRS still a distinct diagnostic entity in 2025?

SRS is a rare syndrome initially described in the 1950s, long before the advent of molecular genetics. SRS was identified based on the association of clinical signs, forming a syndromic entity, characterized by both prenatal and postnatal growth retardation (2, 3). Most affected children are born small for gestational age, experience postnatal growth failure, and present with characteristic features such as relative macrocephaly at birth (a hallmark of the syndrome, indicative of its potential for severe hypoglycemia) and have a protruding forehead, body asymmetry, and significant feeding difficulties in early age. They are also exposed to a higher risk of metabolic syndrome as young adults (4).