# 3-M syndrome: evolution of the phenotype over time

## TL;DR

This paper describes the changing symptoms of 3-M syndrome over time and the role of genetic testing in diagnosing the condition.

## Contribution

The study highlights how the clinical presentation of 3-M syndrome evolves and emphasizes the importance of genetic analysis for accurate diagnosis.

## Key findings

- 3-M syndrome is primarily caused by CUL7 gene variants, but OBSL1 and CCDC8 variants can also lead to the condition.
- Clinical diagnosis is easier in infants, but becomes more complex as children age.
- Next Generation Sequencing and functional studies are crucial for confirming variant pathogenicity.

## Abstract

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.

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.

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.

The online version contains supplementary material available at 10.1186/s13052-025-02172-8.