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Osteogenesis Imperfecta Type VI in Individuals from Northern Canada

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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.

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Acknowledgments

This study was supported by the Shriners of North America and the Fonds de recherche du Québec—Santé. We thank Mark Lepik for the preparation of the figures and Patty Mason for technical assistance. F.R. received support from the Chercheur-Boursier Clinicien program of the Fonds de Recherche du Québec—Santé. This study was supported by the Shriners of North America.

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Authors and Affiliations

  1. Childrens Hospital of Eastern Ontario, Ottawa, ON, Canada

    Leanne Ward

  2. Shriners Hospital for Children and McGill University, 1529 Cedar Avenue, Montreal, QC, H3G 1A6, Canada

    Ghalib Bardai, Pierre Moffatt, Hadil Al-Jallad, Pamela Trejo, Francis H Glorieux & Frank Rauch

Authors
  1. Leanne Ward
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  2. Ghalib Bardai
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  3. Pierre Moffatt
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  4. Hadil Al-Jallad
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  5. Pamela Trejo
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  6. Francis H Glorieux
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  7. Frank Rauch
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Corresponding author

Correspondence to Frank Rauch.

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Conflict of Interests

Frank Rauch received support from the Chercheur-Boursier Clinicien program of the Fonds de Recherche du Québec—Santé and has received consultancy fees from Genzyme Inc and Alexion Inc. Francis H Glorieux has received consultancy fees from Novartis Inc, Amgen Inc and Alexion Inc. Leanne Ward, Ghalib Bardai, Pierre Moffatt, Hadil Al-Jallad, and Pamela Trejo declare no conflict of interest.

Human and Animal Rights and Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from study participants or the legal guardians.

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Ward, L., Bardai, G., Moffatt, P. et al. Osteogenesis Imperfecta Type VI in Individuals from Northern Canada. Calcif Tissue Int 98, 566–572 (2016). https://doi.org/10.1007/s00223-016-0110-1

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  • DOI: https://doi.org/10.1007/s00223-016-0110-1

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