Modeling-based bone formation transforms trabeculae to cortical bone in the sclerotic areas in Buschke-Ollendorff syndrome. A case study of two females with LEMD3 variants.

Buschke-Ollendorff syndrome is a rare autosomal dominant condition caused by pathogenic variants in LEMD3 and characterized by connective tissue nevi and sclerotic bone abnormalities known as osteopoikilosis. The bone phenotype in Buschke-Ollendorff syndrome including osteopoikilosis remains unclear. We investigated bone turnover markers, pelvis and crura X-rays; lumbar spine and femoral neck DXA; bone activity by NaF-PET/CT, bone structure by μCT and dynamic histomorphometry in adults with Buschke-Ollendorff syndrome. Two women aged 25 and 47 years with a BMI of 30 and 32 kg/m2, respectively, were included in the investigation. Bone turnover markers were within normal range. aBMD Z-scores were comparable to that of controls in the lumbar spine and increased at the hip. Radiographies exposed spotted areas in crura and pelvis, and NaF-PET/CT exposed abnormal pattern of irregular shaped NaF uptake in the entire skeleton. In both biopsies, μCT showed trabecular structure comparable to that of controls with stellate shaped sclerotic noduli within the cavity and on the endocortex. Histomorphometric analyses of the sclerotic lesions revealed compact lamellar bone with a normal bone remodeling rate, but partly replaced by modeling-based bone formation. Woven bone was not observed in the nodules. Therefore, while bone turnover and BMD were largely within normal reference range in patients with the Buschke-Ollendorff syndrome, osteosclerotic lesions appear to emerge due to modeling-based bone formation with secondary bone remodeling. These observations indicate that LEMD3 may be important for the activation of bone lining cells leading to modeling-based bone formation.