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Page 282 Jafri et al. J Transl Genet Genom 2022;6:281-9 https://dx.doi.org/10.20517/jtgg.2021.63

Keywords: Lipoprotein receptor-related protein 5 gene (LRP5), osteopetrosis, high bone mass, whole-exome
sequencing (WES), leuprolide acetate

INTRODUCTION
The canonical Wnt signaling pathway is tightly regulated to maintain a balance between bone formation
and resorption. The pathway is activated by the formation of a protein complex consisting of the secreted
signaling protein Wnt, the Frizzled transmembrane receptor, and the co-receptor LDL receptor-related
protein 5 (LRP5). The downstream signaling cascade produced by the complex inhibits proteosomal
degradation of β-catenin. β-catenin subsequently accumulates in the cytoplasm and migrates to the nucleus,
where it acts as a transcriptional co-activator to control Wnt target gene expression that promotes bone
[1]
formation . This signaling cascade is modulated by several protein families including the secreted
inhibitors sclerostin (SOST) and Dikkopf (DKK1), which bind LRP5 receptors to prevent the formation of
[2]
the Wnt-receptor complex .
As a critical regulator of bone formation, LRP5 has been associated with several bone disorders. Mutations
that inactivate the LRP5 gene lead to low bone mass; homozygous mutations cause a severe early-onset
osteoporosis disorder called osteoporosis-pseudoglioma syndrome (MIM 259770), whereas heterozygous
[3]
carriers display a milder form of osteoporosis . LRP5-activating or gain-of-function mutations cause high
bone mass in Autosomal Dominant Osteopetrosis type I (ADO type I; MIM 607634) . Causative variants
[4,5]
for ADO type I cluster in the first β-propeller of the extracellular domain of LRP5, which is an important
region for binding Wnt inhibitory proteins, DKK1 and SOST. The location of these variants prevents the
action of these antagonists and allows for unopposed canonical Wnt signaling that leads to increased bone
formation .
[6]

ADO type I features generalized osteosclerosis that is most notable in the cranial vault. In contrast to other
types of osteopetrosis, ADO type I is not typically associated with fractures. The clinical presentation may
include chronic bone pain, headaches and manifestations of cranial nerve impingement such as blurred
vision. Other indicators of ADO type I are the presence of torus palatinus, enlarged mandible, and negative
[7-9]
buoyancy .
Here we describe the detailed clinical course of a 44-year-old woman who was referred to the National
Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) to identify a cause for her severely
[10]
elevated bone density. Clinical exome sequencing revealed a heterozygous missense mutation in LRP5. The
specific mutation has been reported previously in the context of osteopetrosis and therefore constituted
strong evidence for a diagnosis of ADO type I. Our case is notable for its severity, progression and potential
response to therapy, which provides insight into possible contributing factors and therapeutic options for
patients with ADO type I.

CASE REPORT
Clinical report
The study participant is a 44-year-old woman with Russian Jewish (paternal) and Polish/Ashkenazi Jewish
(maternal) ancestry [Figure 1A]. She reported frequent migrainous headaches and an inability to float in
water present from a young age. At age 24 years, hip and joint pain were noted following the delivery of her
first child [Supplementary Figure 1]. Her pain worsened over time. At approximately 28 years of age, she
gave birth to her second child and noticed changes in the shape of her skull, including thickening of her
forehead and the inside of her mouth and jaw. At age 32, she began experiencing chronic bone pain and