Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review

• Published in: Journal of medical genetics Vol. 59; no. 8; pp. 810 - 816
• Main Authors: Durkin, Anna, DeVile, Catherine, Arundel, Paul, Bull, Mary, Walsh, Jennifer, Bishop, Nicholas J, Hupin, Emilie, Parekh, Susan, Nadarajah, Ramesh, Offiah, Amaka C, Calder, Alistair, Brock, Joanna, Baker, Duncan, Balasubramanian, Meena
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.08.2022; BMJ Publishing Group LTD
• Subjects: Abdomen; Age; Bisphosphonates; bone; Bone matrix; Bones; Calcification; Cell size; Chromosome 5; Collagen; Compression; Extracellular matrix; Fractures; Genes; genetics; Genotype & phenotype; Genotypes; Literature reviews; Long bone; Metabolism; Myopathy; Osteogenesis; Osteogenesis imperfecta; Osteonectin; Parents & parenting; Patients; Phenotypes; Scoliosis; Substantia alba; Vertebrae; United Kingdom > UK; Slovakia
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmedgenet-2021-107942

BackgroundSecreted protein, acidic, cysteine rich (SPARC)-related osteogenesis imperfecta (OI), also referred to as OI type XVII, was first described in 2015, since then there has been only one further report of this form of OI. SPARC is located on chromosome 5 between bands q31 and q33. The encoded protein is necessary for calcification of the collagen in bone, synthesis of extracellular matrix and the promotion of changes to cell shape.MethodsWe describe a further two patients with previously unreported homozygous SPARC variants with OI: one splice site; one nonsense pathogenic variant. We present detailed information on the clinical and radiological phenotype and correlate this with their genotype. There are only two previous reports by Mendozo-Londono et al and Hayat et al with clinical descriptions of patients with SPARC variants.ResultsFrom the data we have obtained, common clinical features in individuals with OI type XVII caused by SPARC variants include scoliosis (5/5), vertebral compression fractures (5/5), multiple long bone fractures (5/5) and delayed motor development (3/3). Interestingly, 2/4 patients also had abnormal brain MRI, including high subcortical white matter changes, abnormal fluid-attenuated inversion in the para-atrial white matter and a large spinal canal from T10 to L1. Of significance, both patients reported here presented with significant neuromuscular weakness prompting early workup.ConclusionCommon phenotypic expressions include delayed motor development with neuromuscular weakness, scoliosis and multiple fractures. The data presented here broaden the phenotypic spectrum establishing similar patterns of neuromuscular presentation with a presumed diagnosis of ‘myopathy’.