SUN-743 - Familial Osteoporosis and Exostotic Bone Disease Associated with ZNF687 Variants: A Mother-Son Case Report

Background Disorders of bone remodeling may present with overlapping phenotypes of osteoporosis and focal bone overgrowth, including exostoses. Germline variants in ZNF687 (Zinc Finger Protein 687) have been implicated in severe forms of Paget disease of bone and giant cell tumor–associated skeletal dysregulation, but their phenotypic spectrum remains incompletely defined.
Objective To describe a mother and her son presenting with osteoporosis and exostotic bone disease associated with heterozygous variants in the ZNF687 gene and to explore the potential role of altered bone remodeling in their clinical phenotype.
Methods
We report two related patients with a combination of low bone mineral density, multiple exostotic bone lesions, skeletal pain, and functional impairment. Comprehensive clinical, radiologic, biochemical evaluations combined with whole exome sequencing were performed. Genomic DNA was isolated from the mother and analyzed using hybridization probes of the genomic target regions (KapaHeredityPanel, Roche). Sequencing of the enriched targets was performed using MGI technology, followed by a bioinformatic study of the DNA sequence obtained and comparison with a reference sequence (GRCh37). The analysis identified the heterozygous missense variants c.2613G>T, p.(Arg871Ser) and c.1741C>T, p.(His581Tyr) in the ZNF687 gene, along with additional variants in genes involved in extracellular matrix integrity and bone remodeling. Longitudinal clinical follow-up included assessment of symptoms, skeletal complications, and response to anti-resorptive therapy.
Results Both patients exhibited early-onset osteoporosis with recurrent or progressive exostotic bone lesions requiring clinical monitoring. Mother’s genetic testing revealed heterozygous ZNF687 variants of uncertain clinical significance for the p.Arg871Ser and pathogenic significance for the p.His581Tyr. Treatment with bisphosphonate therapy was associated with marked and sustained improvement in skeletal pain, functional capacity, and quality of life. Over long-term follow-up exceeding two decades in one patient, no further progression of symptomatic exostoses or need for surgical intervention was observed, and radiographic findings suggested stabilization of exostotic lesions.
Conclusion This familial case highlights an expanded phenotypic spectrum associated with ZNF687 variants, encompassing the coexistence of osteoporosis and exostotic bone disease. The observed clinical stabilization with bisphosphonate therapy suggests that dysregulated bone turnover may represent a modifiable pathway in this condition. These findings underscore the importance of considering ZNF687–related pathology in atypical familial bone remodeling disorders and support further investigation into targeted medical therapies for exostotic bone disease.

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