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Page 286 Jafri et al. J Transl Genet Genom 2022;6:281-9 https://dx.doi.org/10.20517/jtgg.2021.63

Table 1. Bone densitometry Z-scores
Age Lumbar spine Z-score Total hip Z-score
34 7.3 8.0
39 6.5 5.8
44* 6.0 5.8
45 5.9 5.0
45.8* 5.9 5.0
48 6.2 4.8
51* 6.9 5.2

Serial DXA scans were performed by both the patient’s provider as well as the UDP (indicated by *). The scores measured during the time of
leuprolide acetate treatment are shown in gray. UDP: Undiagnosed Diseases Program.

Figure 3. Cranial volume and tonsillar descent measurements. (A-B) Intracranial bone volume was measured by CT scan-based 3D
reconstruction. (A) The software outlined the patient’s intracranial space in 5 to 10 slices of each CT scan. (B) The software calculates
volume using the outlined area and slice thickness. (C-F) Serial CT scans were used to measure the descent of the cerebellar tonsil. (A-
F) Measurements performed on CT scans taken during leuprolide acetate treatment are shown in gray. CT: Computed tomography.

DISCUSSION
Mutations in LRP5 have previously been reported to cause the rare osteopetrosis disorder ADO type I. The
symptomatic manifestations of elevated bone mass vary among affected individuals, but may include
chronic bone pain, headaches, blurry vision, enlarged mandible, torus palatinus, resistance to bone
fractures, and negative buoyancy . Affected individuals are often unaware of the elevated density of their
[7,8]
bones until revealed by an incidental radiology study.

Here we present a patient with a severe form of ADO type I, including a thickened calvarium with
intracranial volume restriction and an anecdotal response to off-label therapy. The previously-described
causative mutation is located in the fourth exon of the LRP5 gene and affects the first β-propeller domain, a
region important for binding inhibitory proteins. Protein modeling performed by Gregson et al. suggested
that the degree of protein structure alteration and the resulting effect on SOST-LRP5 binding correlates