title: Osteogenesis Imperfecta Type VI in Individuals from Northern Canada.
abstract: Osteogenesis imperfecta (OI) type VI is a recessively inherited form of OI that is caused by mutations in SERPINF1, the gene coding for pigment-epithelium derived factor (PEDF). Here, we report on two apparently unrelated children with OI type VI who had the same unusual homozygous variant in intron 6 of SERPINF1 (c.787-10C>G). This variant created a novel splice site that led to the in-frame addition of three amino acids to PEDF (p.Lys262_Ile263insLeuSerGln). Western blotting showed that skin fibroblasts with this mutation produced PEDF but failed to secrete it. Both children were treated with intravenous bisphosphonates, but the treatment of Individual 1 was switched to subcutaneous injections of denosumab (dose 1 mg per kg body weight, repeated every 3 months). An iliac bone sample obtained after 5 denosumab injections (and 3 months after the last injection) showed no change in the increased osteoid parameters that are typical of OI type VI, but the number of osteoclasts in trabecular bone was markedly increased. This suggests that the effect of denosumab on osteoclast suppression is of shorter duration in children with OI type VI than what has previously been reported on adults with osteoporosis.
authors.affiliation: Childrens Hospital of Eastern Ontario, Ottawa, ON, Canada.
authors.forename: Leanne
authors.initials: L
authors.lastname: Ward
authors.affiliation: Shriners Hospital for Children and McGill University, 1529 Cedar Avenue, Montreal, QC, H3G 1A6, Canada.
authors.forename: Ghalib
authors.initials: G
authors.lastname: Bardai
authors.affiliation: Shriners Hospital for Children and McGill University, 1529 Cedar Avenue, Montreal, QC, H3G 1A6, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Moffatt
authors.affiliation: Shriners Hospital for Children and McGill University, 1529 Cedar Avenue, Montreal, QC, H3G 1A6, Canada.
authors.forename: Hadil
authors.initials: H
authors.lastname: Al-Jallad
authors.affiliation: Shriners Hospital for Children and McGill University, 1529 Cedar Avenue, Montreal, QC, H3G 1A6, Canada.
authors.forename: Pamela
authors.initials: P
authors.lastname: Trejo
authors.affiliation: Shriners Hospital for Children and McGill University, 1529 Cedar Avenue, Montreal, QC, H3G 1A6, Canada.
authors.forename: Francis H
authors.initials: FH
authors.lastname: Glorieux
authors.affiliation: Shriners Hospital for Children and McGill University, 1529 Cedar Avenue, Montreal, QC, H3G 1A6, Canada. frauch@shriners.mcgill.ca.
authors.forename: Frank
authors.initials: F
authors.lastname: Rauch
mesh_terms: D000293:Adolescent; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D002170:Canada; D002648:Child; D002675:Child, Preschool; D000069448:Denosumab / Q000627:therapeutic use; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D009414:Nerve Growth Factors / Q000235:genetics*; D010013:Osteogenesis Imperfecta / Q000188:drug therapy* / Q000235:genetics*; D015843:Serpins / Q000235:genetics*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D050071:Bone Density Conservation Agents; D000069448:Denosumab; D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor
keywords: Children; Fractures; Osteogenesis imperfecta; Pigment-epithelium derived factor; SERPINF1