SUN-711 Clinical Presenting Features, Biochemical, Radiological, and Genetic Characteristics of Four Male Patients with Osteopetrosis from a Canadian Tertiary Center.

Abstract Disclosure: M.H. Alabdely: None. D.S. Ali: None. M. Brandi: None. A.A. Khan: None. Background: Osteopetrosis (OPT) is a rare bone disease associated with decreased osteoclast-mediated bone resorption. OPT is caused by various mutations which may be due to autosomal dominant, autosomal recessive, or x-linked recessive forms. OPT can cause fragility fractures, spinal cord compression, hydrocephalus, and cranial nerve entrapment. A decrease in the bone marrow space leads to pancytopenia and extra medullary hematopoiesis with hepatosplenomegaly. Hearing impairment, mandibular osteomyelitis and osteoarthritis may also occur. Pathological fractures of long bones may occur due to bone sclerosis. Infantile OPT is treated with bone marrow transplant, while adults receive supportive care. Methods: We retrospectively reviewed charts of all patients at our Canadian Bone Research and Education Centre to identify the presenting features of OPT in our patient population. Results: We identified four males with OPT, mean age 50 years, diagnosed with OPT. Three patients (75%) were diagnosed incidentally with imaging and high bone mineral density (BMD). Bone pain was present in 75% of patients. Fragility fractures, decreased vision, hearing impairment, osteoarthritis, headache, and dizziness were present in 25%. No dental, or hematological abnormalities were observed. Two patients had a diffusely sclerotic appearance of the axial skeleton. One patient had sclerotic changes of the spine suggestive of rugger jersey spine and bony sclerosis affecting the entire pelvis and other ribs. Low vitamin D was found in 50%. One patient had elevated 24-hour urine calcium, and another had high alkaline phosphatase level. Two patients have family history of OPT or high BMD. Genetic testing revealed two likely pathogenic heterozygous variants in the CLCN7 gene (c.2332-1G>A and c.869C>T,p.Ser290Phe) previously reported in the literature. Additionally, novel heterozygous VUS variants in PLEKHM1 gene c.100G>A(p.Val34Met) and OSTM1 gene c.313A>G(p.Ser105Gly) were identified amongst the genes associated with OPT in one patient. We also identified a novel heterozygous VUS variant in the CLCN7 gene c.2335delG(p.Val779Serfs*4) associated with AD OPT type2. One patient received IV zoledronate, while the others received supportive care. Conclusion: We present four males with OPT. The presenting clinical features most noted were bone pain being the most prevalent symptom (75%), other clinical features included vision and hearing impairment, headaches, osteoarthritis, and fragility fractures, each occurring in 25% of cases. The one patient with a fragility fracture was treated with IV zoledronate, while the others received supportive care. Genetic testing identified likely pathogenic variants in the CLCN7 gene in 50% of cases. Additionally, we discovered three novel variants in CLCN7, PLEKHM1, and OSTM1 that could be pathogenic. Presentation: Sunday, July 13, 2025