Russell–Silver syndrome: A case series highlighting clinical heterogeneity, molecular diagnosis, and growth hormone response

Russell–Silver syndrome (RSS) is a rare imprinting disorder characterized by intrauterine growth restriction, proportionate short stature, relative macrocephaly, feeding difficulties, and distinctive facial features. The Netchine– Harbison clinical scoring system facilitates early clinical diagnosis, while molecular testing confirms the etiology in approximately 60% of cases. Growth hormone (GH) therapy improves height outcomes, although responses vary. We describe the clinical characteristics, molecular findings, and response to GH therapy in four children diagnosed with RSS. Case 1 presented with intrauterine growth restriction and hemi-hypoplasia, with molecular confirmation of loss of methylation at imprinting region 1 (IC1) and an 11q22.3 deletion; GH therapy was initiated at 2 years of age and is ongoing with improvement in height. Case 2, an extremely preterm infant with severe growth failure, carried an insulin-like growth factor-2 gene mutation (RSS type 3) and showed improved growth following GH therapy. Case 3 presented with failure to thrive, facial dysmorphism, and an atrial septal defect; IC1 hypomethylation was identified, and the child demonstrated good catch-up growth with GH therapy. Case 4, an adolescent girl, presented late with developmental delay and myoclonic dystonia; maternal uniparental disomy of chromosome 7 was detected. She received GH therapy for 5 years with limited growth response. This case series highlights the marked clinical and molecular heterogeneity of RSS, underscores the importance of clinical suspicion supported by molecular testing, and suggests that early initiation of GH therapy may optimize growth outcome.