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Jafri et al. J Transl Genet Genom 2022;6:281-9 https://dx.doi.org/10.20517/jtgg.2021.63 Page 287

[8]
directly with the severity of the ADO type I phenotype . The p.A242T mutation identified in our patient is
predicted by computational model to alter the packing of the LRP5 structure and destabilize the SOST
[8]
binding site . Another ADO type I associated variant, p.N198S, is predicted to directly disrupt the SOST
[8]
binding site. These two variants are associated with a severe ADO type I disease course . Reflecting the
structural impact of these mutations, the p.N198S mutation has resulted in severe bone phenotypes with a
BMD Z-score range from +5.6 to +12.2, while the p.A242T has been reported to cause a range of BMD Z-
scores from +3.1 to +10.7 . Although the variant’s impact on the protein appears to predict how high BMD
[8]
scores can reach, there is considerable variability among patients with the same variant, suggesting that
other factors may play a role in determining the severity of a patient’s disease.

The patient’s clinical course is of interest in that worsening symptoms seem to coincide with her
pregnancies, indicating that sex hormones may influence the disease’s progression. The onset of her bone
pain and subsequent symptoms coincided with pregnancy and the delivery of her first child. A change in
her skull shape, frontal bossing and an enlarged mandible were noted around the delivery of her second
child. Progesterone and estrogen, sex hormones necessary for maintaining pregnancy, rise as pregnancy
progresses. Estrogen is a well-known regulator of bone metabolism that directly interacts with bone cells to
decrease bone remodeling and resorption as well as maintain bone formation . Progesterone acts directly
[14]
on cell surface receptors to increase bone production as well [15,16] . We posit that the increased estrogen
and/or progesterone levels from the proband’s two pregnancies may have exacerbated the LRP5-associated
increase in bone mass. Although we were unable to collect data following the onset of menopause, a
previous study suggested menopausal hormonal changes may also affect bone metabolism. Balemans et al.
reported a female ADO type I patient who showed a 5% reduction in bone densitometry values between the
[17]
ages of 50 and 55 after passing through menopause at 52 . While additional studies are needed to assess the
true impact of sex hormone changes on ADO type I bone mass growth, this may be an important factor to
consider with patients as it pertains to the management of their disease.

Currently, there are no recommended treatment options beyond pain management for ADO type I patients.
In an effort to identify an effective therapy for this patient, leuprolide acetate and anastrozole were trialed in
an empiric, off-label fashion. Leuprolide acetate is a synthetic gonadotropin-releasing hormone or
luteinizing hormone-releasing hormone (GnRH or LH-RH) analog indicated for treating anemia,
precocious puberty, endometriosis, and advanced prostate cancer. It has a known side effect of decreasing
bone mineral density by suppressing the production of sex hormones . Anastrozole is a nonsteroidal
[18]
aromatase inhibitor used in the treatment of breast cancer, which blocks the production of estrogen. It also
has a side effect of causing decreased bone mineral density . While anastrozole was ineffective, leuprolide
[19]
acetate reportedly had a positive effect. The treatment period (age 42.6-46.7) coincided with an
improvement of symptoms, a mild decrease and stabilization of bone density scores, a normalization of
bone formation marker levels, and an apparent change in the rate of intracranial volume loss suggesting
stabilization of skull mineralization. Based on these observations, leuprolide acetate should be considered
for a more rigorous evaluation of efficacy in the treatment of ADO type I.

In summary, we present a detailed clinical description of a patient with a severe presentation of ADO type I
due to a heterozygous missense mutation in LRP5. Our results suggest that sex hormones may play an
influential role in this disorder and should be considered when discussing disease management with
patients. We also provide anecdotal evidence that leuprolide acetate may benefit patients with ADO type I.
These observations raise the question of its utility for male or younger, asymptomatic patients with ADO
type I and patients with other forms of osteopetrosis. Further studies are needed to evaluate all of these
potential applications for leuprolide acetate and to identify new approaches to slow bone growth and