3-M syndrome: evolution of the phenotype over time

BACKGROUND: 3-M syndrome is an autosomal recessive disease characterized by short stature, facial dysmorphism and skeletal anomalies. To date, biallelic pathogenic CUL7 variants are responsible for the majority of cases, but biallelic deleterious changes in OBSL1 and CCDC8 can also establish the diagnosis. CASES PRESENTATION: We report two unrelated newborns showing clinical signs compatible with 3-M syndrome and we describe the evolution of the phenotype of the first patient over time. Molecular analysis identified two compound heterozygous CUL7 variants in the first individual and a homozygous CUL7 variant in the second one. CONCLUSIONS: We reviewed the literature highlighting the clinical differences between patients with variants in CUL7, OBSL1 and CCDC8. Our paper highlights how the clinical diagnosis of 3-M is easier in the first months of life, while in older children the phenotype becomes increasingly nuanced. It also underlines the clinical relevance of Next Generation Sequencing and functional studies, which may be necessary to confirm the pathogenicity of some variants, becoming an essential part of the multidisciplinary management of patients.