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Jafri et al. J Transl Genet Genom 2022;6:281-9 Journal of Translational
DOI: 10.20517/jtgg.2021.63
Genetics and Genomics

Case Report Open Access

Potential therapeutic response in a severe case of
autosomal dominant osteopetrosis type I

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Syed Maisam Jafri , Elizabeth A. Burke , David R. Adams , Colleen Evans , Dorothy Bulas , Stuart A.
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Weinerman , Kristen Pan , Michael T. Collins , Thomas C. Markello , Gilbert Vezina , William A. Gahl ,
Camilo Toro 1
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NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Human Genome Research Institute,
National Institutes of Health, Bethesda, MD 20892, USA.
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Endocrinology at Great Neck, Northwell Health Physician Partners, Great Neck, NY 11021, USA.
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National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
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Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National
Institutes of Health, Bethesda, MD 20892, USA.
Correspondence to: Dr. Camilo Toro, NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National
Human Genome Research Institute, National Institutes of Health, 10 Center Dr., Room 3-2251, Bethesda, MD 20892, USA. E-
mail: toroc@mail.nih.gov
How to cite this article: Jafri SM, Burke EA, Adams DR, Evans C, Bulas D, Weinerman SA, Pan K, Collins MT, Markello TC,
Vezina G, Gahl WA, Toro C. Potential therapeutic response in a severe case of autosomal dominant osteopetrosis type I. J Transl
Genet Genom 2022;6:281-9. https://dx.doi.org/10.20517/jtgg.2021.63
Received: 23 Dec 2021 First Decision: 9 Feb 2022 Revised: 15 Feb 2022 Accepted: 29 Mar 2022 Published: 6 Jun 2022
Academic Editor: Bridget Bax Copy Editor: Jia-Xin Zhang Production Editor: Jia-Xin Zhang
Abstract
The low-density lipoprotein receptor-related protein 5 gene (LRP5), which encodes a coreceptor within the
canonical Wnt signaling pathway, plays a crucial role in bone mass regulation and has been associated with several
bone disorders. Autosomal dominant osteopetrosis type I (ADO type I, OMIM 607634) is a rare disease caused by
heterozygous, gain-of-function mutations in LRP5. Here we describe a 44-year-old female who presented with
thickened calvarium, elevated bone density, torus palatinus, mandibular exostoses, enlarged mandible, and
disabling headaches and bone pain. Exome sequencing revealed a previously reported heterozygous missense
variant in the LRP5 gene (p.A242T). Post-diagnosis cranial vault volume measurement by computed tomography
3D reconstruction demonstrated decreasing intracranial volume over time. Off-label use of leuprolide acetate was
associated with apparent stabilization of skull mineralization. This report documents a severe example of ADO
type I and provides anecdotal evidence of the utility of therapy in need of formal evaluation.

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0
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