55. Autosomal Dominant High Bone Mass Syndrome Presenting Before Skeletal Maturity

Abstract

Background: Molecular genetics has enabled mutations underlying the high bone mass (HBM) phenotype to be identified. However, the patho-genesis of this syndrome remains unclear. Additionally, recent studies have focussed on HBM in adults, with limited research in children. Here, we recruited an index case (48-year-old, female) and her child (10-year-old) with HBM phenotype into the Wellcome Trust Clinical Research Facility (WTCRF) DINAG (Databases to Identify Novel Anabolic Genes) study. History & Progress: A 10-year-old (y/o) participant in the Cambridge Baby Growth Study (CBGS) cohort was referred to the Addenbrooke's bone clinic after the CBGS team discovered an abnormality on his whole body DXA scan. His total body BMD was +4.4 standard deviations (SD) above the 10 y/o mean despite him being of unremarkable weight and height (+0.84 SDs). His only significant past history was pre-school speech impediment associated with 'blocked auditory canals', resolving without surgery. His mother had noted his proficiency during rugby matches, particularly in contact situations. High-resolution peripheral quantitative computed tomography (pQCT; Xtreme CT, Scanco) showed an increased bone surface area and average bone density in the radius and tibia, compared to local age-matched reference values. At 45 y/o his mother also attended for total body DXA, yielding a Z score +3.1 despite normal BMI of 23.2 kg/m2 (total body fat -0.3SD). T-scores for the right and left femur, and L2-4 were all above the mean (1.4, 1.8, and 2.4 respectively). Symmetrical painless bony prominences were noted on the dorsum of her hands (abnormalities also reported in a maternal aunt), with milder prominence bilaterally in malleoli, tibial plateaus, iliac crests, and elbows. Oral examination revealed tori mandibularii (<3mm diameter). She reported difficulty with swimming and buoyancy. Her two other children had normal bone density. There was no family history of fractures or bone pain. Bilateral X-ray imaging of the mother's hands and knees showed cortical thickening and increased trabecular density. Xtreme CT of the radius and tibia demonstrated increased trabecular bone volume: tissue volume ratio, with increased numbers and thickness of trabeculae, and increased peripheral trabecular bone. Conclusion: These results confirm HBM syndrome in the index case and her son, with an autosomal dominant pattern of inheritance, although whole exome sequencing for common HBM variants was negative. Monitoring the trajectory of bone mineral density accrual in a pre-pubertal boy with HBM will provide insights into the natural history of this rare condition.