Catch-up of bone mineral density in osteoporosis-pseudoglioma syndrome

Abstract

Skeletal fragility during childhood induces fractures due mainly to a decrease in bone quantity and also an alteration of bone quality. Osteoporosis-pseudoglioma syndrome (OPPG, MIM 259770) was discovered in the last century and is a very rare genetic disorder with an autosomal recessive mode of inheritance, characterized by congenital or infancy-onset visual loss and skeletal fragility diagnosed during childhood due to a severe defect of bone accrual during growth. More than 50 cases have now been described. This syndrome can lead to severe disability and chronic bone pain. The gene mutated and inactivated in OPPG is LRP5 (LDL receptor-related protein 5), a Wnt membrane co-receptor expressed in osteoblasts and many other cell types. LRP5 plays a pivotal role in bone accrual and skeletal remodelling by controlling bone formation through activators such as Wnt proteins or inhibitors such as DKK1. The lack of a functional LRP5 leads to a severe defect of bone formation by osteoblasts, very early in the process of bone growth and bone accrual. The main differential diagnoses of OPPG are osteogenesis imperfecta and child abuse; these should be known to clinicians. Eye examination, coupled to bone phenotype and research of LRP5 mutation, is key to diagnose OPPG. Chronic pains with severe functional disability due to repeated fractures are the main problems to manage. Clinicians should normalize the serum level of 25(OH) vitamin D and calcium diet in parallel to giving bisphosphonates during childhood. Bisphosphonates (the main studies have been done with pamidronate) allow fracture prevention, catch-up of bone mineral density, and improvement in mobility in children with OPPG. New drugs favouring osteoblast function and osteoclast inhibition are potential candidates to treat OPPG.