Osteogenesis Imperfecta, Type Xvii

A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type XVII (OI17) is caused by homozygous mutation in the SPARC gene (182120) on chromosome 5q33.

Clinical Features

Mendoza-Londono et al. (2015) reported 2 unrelated girls with a clinical diagnosis of osteogenesis imperfecta type IV (OI4; 166220) in whom mutations in the SPARC gene were identified. One was a 14-year-old girl of North African origin who sustained her first fracture at 15 months of age, when she broke her right femur in a fall while trying to stand. X-rays at 19 months showed multiple vertebral compression fractures of the thoracic spine and kyphoscoliosis. By 4.4 years of age, she had sustained 10 long-bone fractures. Serum biochemistry was normal. Despite treatment with intravenous pamidronate, bone mineral density (BMD) remained low and scoliosis continued to increase, necessitating spinal fusion at 6.7 years of age. Other features included mild joint hyperlaxity, underdeveloped and weak muscles of the lower extremities, and bowing of both humeri, as well as expressive and comprehensive speech delay. At 14 years of age, the patient had short stature and had sustained approximately 1 long-bone fracture per year; she used a wheelchair for all mobility, having never achieved independent walking. Her parents had lumbar spine BMDs in the normal to low-normal range, and normal peripheral quantitative CT scans of the forearm. The second girl was born of consanguineous Indian parents and had left hip dislocation at age 10 weeks. She sustained her first low-trauma fracture at 5 years of age, a transverse femur fracture after a low-impact fall, and had 5 more fractures over the following 2 years. MRI of brain and spine at age 4 showed a large spinal canal with syrinx from T10 to T11, generalized platyspondyly, and thoracic kyphosis. Skeletal x-rays at age 6 showed compression fractures of most thoracic and lumbar vertebrae as well as mild kyphoscoliosis, and she had decreased lumbar spine BMD. Analysis of an iliac bone sample excluded a mineralization disorder, but was consistent with hypermineralization on the material level. Other features in this patient included motor delay, muscle hypotonia, lower extremity weakness, decreased calf muscle mass, joint hyperlaxity, and soft skin. No parent of the affected girls had a history of fractures.

Molecular Genetics

In 2 unrelated girls with OI17, Mendoza-Londono et al. (2015) performed whole-exome sequencing and identified homozygosity for missense variants in the SPARC gene, R166H (182120.0001) and E263K (182120.0002), respectively. No variants were detected in genes known to be associated with dominant or recessive OI. The mutations were present in heterozygosity in the unaffected parents and were not found in an in-house exome database or the dbSNP, 1000 Genomes Project, NHLBI/NHGRI Exome Project, or ExAC databases. Noting that SPARC is dynamically produced in blood vessels during central nervous system development, the authors suggested that an episode of intraventricular hemorrhage observed in the immediate postnatal period in the girl of North African origin could be related to the defect in SPARC.