Hallermann-Streiff syndrome (HSS) is a rare developmental disorder characterized by premature aging, congenital cataracts, microphthalmia, hypotrichosis, beaked nose, skin atrophy, micrognathia, dental anomalies and proportionate short stature. Only a minority of HSS patients show intellectual disability. Since its first description in the mid-50s no causative gene has been identified and therefore, the molecular basis of HSS is still unknown. Recently, however, whole-exome sequencing studies in parent-index trios and single cases have detected the first mutation underlying HSS in the SMC2 gene. SMC2 belongs to the family of the structural maintenance of chromosome proteins and forms a complex with SMC4 involved in sister chromatid condensation, mitotic chromosome integrity, gene expression, and DNA repair. To shed light into the molecular mechanisms underlying HSS, we performed gene expression profiling in cultured skin fibroblasts. Transcriptome analysis revealed marked alterations in the expression levels of several genes associated with chromosome segregation, mitotic nuclear division, cell cycle DNA replication and double-strand break repair. In addition, SMC2 mRNA expression revealed a significant down-regulation in patients’ cells correlating with the mutation. Furthermore, a significant reduction in SMC2 and SMC4 protein levels was observed in patients’ primary fibroblasts. As short telomeres are considered as a hallmark of aging, their length was assessed in HSS patients. Remarkably, patients’ cells showed telomere shortening. Our findings add for the first time new insights into the pathophysiology of HSS.