Fragile Bones Secondary to SMURF1 Gene Duplication

Studies on mice have shown that the Smad Ubiquitin Regulatory Factor-1 (SMURF1) gene negatively regulates osteoblast function and the response to bone morphogenetic protein in a dose-dependent fashion (Chan et al. in Mol Cell Biol 27(16):5776-5789, https://doi.org/10.1128/MCB.00218-07, 2007; Yamashita et al. in Cell 121(1):101-113, https://doi.org/10.1016/j.cell.2005.01.035, 2005). In addition, a tumorigenic role for SMURF1 has been implicated due to the interference with apoptosis signals (Nie et al. in J Biol Chem 285(30):22818-22830, https://doi.org/10.1074/jbc.M110.126920, 2010; Wang et al. in Nat Commun 5:4901, https://doi.org/10.1038/ncomms5901, 2014). A 10-year-old girl with a history of severe developmental delay, infantile seizures, and B-cell lymphoma, in remission for approximately 3.5 years, was referred to the metabolic bone clinic for fractures and low bone mineral density. Array comparative genomic hybridization revealed a pathogenic microduplication in chromosome 7 at bands 7q21.3q22.1 that encompasses the SMURF1 gene. The clinical features of this child are congruous with the phenotype as ascribed excess Smurf1 mutations in mice. This is the first case description of osteoporosis in a child secondary to a microduplication involving SMURF1 gene.