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Page 284 Jafri et al. J Transl Genet Genom 2022;6:281-9 https://dx.doi.org/10.20517/jtgg.2021.63

abdominal pain that resolved with VP shunt replacement.

The continuing bone evaluation included an iliac crest bone biopsy. The cortex was found to be markedly
thickened, with a cortical width more than twice the upper limit of the reference range. Dense lamellar bone
and cortical porosity appeared to be reduced. Osteons were found to be quiescent, while osteoblast and
osteoclast morphology was normal. Osteons with active osteoclasts and eroded surfaces were occasionally
seen. Cancellous bone, adjacent to endocortical surface, exhibited thickened trabeculae with normal
lamellar structure. Residual calcified cartilage was not found.

At the age of 44, the patient was evaluated for the first time at the NIH. Her height was at the 5th centile,
while head circumference was at the 98th centile. Hand and palm lengths were at the 1st and < 1st centiles,
respectively. Physical examination was notable for bilateral bony protrusions posterior to the second molars
that caused crowding of the lower front teeth [Figure 1B]. The presence of torus palatinus, a non-specific
but characteristic sign of osteopetrosis, was also noted [Figure 1C]. The mandible was square-shaped and
enlarged [Figure 1D-E]. The calvarium was thickened [Figure 1E]. Palpable ridges were appreciable on her
forehead. The patient had essentially normal hearing for speech and pure tones bilaterally except for mild
high-frequency hearing loss confined to 6000-8000 Hz in the left ear. She reported constant dull pain with
intermittent bouts of shooting pains, in addition to less intense systemic bone pain. Even though the patient
had trouble staying asleep and reported waking up 15-20 times in the night, she had no difficulty falling
asleep. She denied psychological problems and reduced her pain with non-steroidal anti-inflammatory
drugs. At a follow-up evaluation, she reported that she had a lumbar 4-5 spinal fusion performed at the age
of 51 years.

At the time of the patient’s first evaluation at the NIH, her 20-year-old son was discovered to have the
beginning of a torus palatinus and increased bone density with Z-scores of +3.7 at the hip and +3.8 at the
spine. Her 16-year-old daughter’s Z-scores were also elevated at +5.3 at the hip and +4.5 at the spine despite
having no other symptoms of ADO type I. The proband’s mother also reported some bony growth on her
upper and lower gums, a square jaw, and was determined to have high bone density with DXA Z-scores of
+4.3 at the hip and +5.5 at the spine at the age of 65.

Genetic analysis
Exome sequencing was conducted on the proband, her two children, two sisters, husband, and mother. The
presence of the heterozygous missense NM_002335.2: c.724G>A (p.A242T) variant in the fourth exon of the
LRP5 gene was revealed. Both of the proband’s children and her mother were also found to have the same
LRP5 mutation and are affected by the disorder confirming an autosomal dominant mode of inheritance
[Figure 1A]. This variant has been previously reported in several individuals in association with ADO type
[13]
I [8,11,12] , and is not present in GnomAD v2.1.1 .

Biochemical analysis
Markers of bone formation and bone resorption were serially measured in the patient’s serum and urine
[Figure 2A]. Notably, the two markers of bone formation, procollagen I intact N-terminal and bone-specific
alkaline phosphatase, were elevated above normal ranges and subsequently reduced during leuprolide
acetate treatment (indicated by gray color) [Figure 2A-C]. The markers of bone resorption, NTX-
telopeptide and beta-C-terminal telopeptide (β-Ctx), consistently remained within normal ranges
[Figure 2A].