To the Editor: Osteogenesis Imperfecta (OI), characterized by decreased bone density leads to bone fragility and deformity [1]. We report a novel homozygous splice site variant in the SPARC gene from India and the sixth case in the world with a severe OI phenotype.
A three-year-old boy born to consanguineous parents, weighing 3.2 kg had no birth fractures or limb deformities but presented with severe motor delay. His first fracture occurred at 1.3 y in his right femur, followed by 15 more fractures in the lower limbs. Physical examination revealed normal dentition, mild blue sclera, and joint hyperlaxity (Wynn-Davies) score of 5/5. His weight was 10 kg, and his height was 81 cm.
Radiographs showed multiple vertebral compression fractures, thoracic kyphosis, and thoracolumbar scoliosis. His bone density was 0.237 g/cm2 at the radius and 0.203 g/cm2 at the lumbar spine on the DXA scan. His Quality of life (PedsQLTM4.0) [2] assessment revealed a 68.75% physical functioning score, 40.38% psychosocial score, and 54.56% of health-related quality of life, which was poor.
A homozygous novel variant c.451+1G>A (NM_001309444.1) was identified in intron 6 of the SPARC gene, which was predicted as disease-causing by MutationTaster and class 5 splice variant causing exon skipping by VarSEAK tool. Segregation analysis showed parents and another sibling as heterozygous.
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.
To conclude, muscular weakness with significant generalized hypotonia associated with low trauma fractures and early scoliosis seems to be an initial presentation in the previously published cases resulting in a significant motor delay and should alert the clinician to SPARC gene associated OI.
References
Marini JC, Forlino A, Bächinger HP, et al. Osteogenesis imperfecta. Nat Rev Dis Primers. 2017;3:17052.
Klatchoian DA, Len CA, Terreri MTRA, et al. Quality of life of children and adolescents from São Paulo: Reliability and validity of the Brazilian version of the Pediatric Quality of Life Inventory version 4.0 Generic Core Scales. J Pediatr (Rio J). 2008;84:308–15.
Mendoza-Londono R, Fahiminiya S, Majewski J, et al. Recessive osteogenesis imperfecta caused by missense mutations in SPARC. Am J Hum Genet. 2015;96:979–85.
Durkin A, DeVile C, Arundel P, et al. Expanding the phenotype of SPARC -related osteogenesis imperfecta: Clinical findings in two patients with pathogenic variants in SPARC and literature review. J Med Genet. 2021;59:810–6.
Funding
Department of Biotechnology, Government of India, grant number BT/IN/SWEDEN/09/VM/2017 and Indian Council of Medical Research, grant number 54/9/2015-HUM BMS.
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Selina, A., James, D. & Madhuri, V. A Novel Biallelic Splice Site Variant in the SPARC Gene Causing Severe Osteogenesis Imperfecta. Indian J Pediatr 90, 626 (2023). https://doi.org/10.1007/s12098-023-04541-9
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DOI: https://doi.org/10.1007/s12098-023-04541-9