Genetic factors play an important role in osteoporosis. Several monogenic forms of osteoporosis have been recognized. The most common is osteogenesis imperfecta (OI) in which heterozygous mutations in the genes encoding type 1 collagen are responsible for ~90% of the cases. Several rare autosomal recessive forms of OI have also been described. In these the defects lie in proteins involved in posttranslational modification of type 1 collagen. Recent studies have also identified several forms not related to type 1 collagen. The WNT-signalling pathway is of key importance for skeletal health, activation leading to increased and inhibition leading to decreased bone mass. Mutations in LRP5, encoding a co-receptor for the pathway, cause the autosomal recessive osteoporosispseudoglioma syndrome or early-onset osteoporosis. Recently heterozygous loss-of function mutations in the WNT1 gene were shown to lead to early-onset osteoporosis while homozygous WNT1 mutations resulted in severe infancy-onset osteoporosis. The first X-chromosomal form of osteoporosis, resulting from mutations in the gene encoding plastin 3 (PLS3), was described in 2013. PLS3-osteoporosis has its onset in childhood and results in recurrent peripheral fractures, low BMD, vertebral compression fractures, and significant height loss in adulthood. Males are in more severely affected than females. PLS3 may be linked to osteocyte dendrite function and skeletal mechanosensing. Future studies are needed to elucidate the role of WNT1 and PLS3 in early-onset osteoporosis and to define optimal therapy for affected individuals.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology