Bone Abstracts

Objectives: We recently identified a heterozygous missense mutation c.652T→G (p. C218G) in WNT1 as the cause of severe primary osteoporosis (Laine et al. New Engl J Med 2013). The mutated WNT1 reduces activation of the canonical WNT1/β-catenin-signaling, resulting in decreased osteoblastic function. The mutation was originally identified in a large Finnish family presenting with dominantly inherited, early-onset osteoporosis, with affected adult patients showing reduced bone mineral density (BMD) and high incidence of vertebral compression fractures. The objective of this study was to examine skeletal phenotypes and possible progression with age in mutation-positive pediatric patients.

Methods: This study included six subjects below the age of 18 years who were found to harbor the heterozygous p. C218G WNT1 mutation, as confirmed by Sanger sequencing. Medical records were reviewed for fractures, medications and possible other illnesses. DXA and radiographic imaging were used to evaluate BMD and skeletal phenotypes. Peripheral blood and urine samples were obtained to exclude secondary causes and to assess calcium, phosphate and vitamin D levels.

Results: The six patients, three girls and three boys, ranged in age from 12 to 17 years, and had normal growth. Childhood low-energy fractures were common. All patients had BMD Z-scores below the normal mean, and there was a clear progression of loss in BMD with age. Radiographs revealed loss in vertebral height, osteopenic appearance and in three patients, abnormally thin fibulae and overtubulation of tibiae. Blood and urine samples showed no abnormalities in calcium, phosphate or vitamin D levels; bone turnover markers were normal.

Conclusions: This study confirms that skeletal changes in dominantly inherited WNT1 osteoporosis are established already at early childhood and progress with age. Early intervention and possible treatment could significantly improve bone health in affected individuals and prevent severe fractures. In light of these results genetic testing of children to affected parents is recommended. Optimal treatment of WNT1 osteoporosis in children remains to be established in future clinical studies.

Disclosure: The authors declared no competing interests.