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

Abstract

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’.

A Novel Biallelic Splice Site Variant in the SPARC Gene Causing Severe Osteogenesis Imperfecta

“…Delayed motor development with neuromuscular weakness, scoliosis and multiple compression fractures as common phenotypes in SPARC gene mutation have been reported recently and expand the phenotypic spectrum of similar neuromuscular patterns with a presumed diagnosis of myopathy [3,4]. Our child's significant motor delay and hypotonia through grade 3 power are consistent with previous reports.…”

CYP27A1 deficiency promoted osteoclast differentiation

“…The BGN also directly collaborates with TNF-α and RANKL to control the bone mass and osteoclastogenesis ( Kram et al, 2017 ). The SPARC is required for the calcification of collagen in bone, and is also involved in maintaining cell shape ( Durkin et al, 2022 ). COL1A2 encodes pro-alpha2 chain of type I collagen, and its mutations cause the osteogenesis imperfecta ( Makitie et al, 2019 ).…”

Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and Therapeutic Approaches

“…Both type XVII and type XVIII OI patients share a history of repeated fractures and exhibit a clinical severity ranging from moderate to severe. , Type XVII is characterized by impaired lower-extremity muscular strength and delayed speech or motor development. , On the other hand, type XVIII OI presents congenital lower extremity curvature, vertebral collapse, and numerous fractures. Patients with type XX OI have mutations associated with the WNT1 signaling pathway, similar to those seen in type XV patients …”