Endocrine Abstracts

A 27-year-old woman with familial exudative vitreoretinopathy (FEVR) experienced multiple childhood fractures, including wrist (aged 7y), hip (aged 10y) and numerous vertebrae. She had low bone mineral density (BMD) (Z scores < -2.5 at multiple sites aged 9; persistently low BMD as an adult) and was short (height below 1st centile). Other features included an unusual facies and mild intellectual impairment. Her mother also had FEVR, dental hypoplasia, mild intellectual impairment, and height below 1st centile. At age 36 her mother fractured her humerus, scapula and clavicle after a fall from standing height; and she had profoundly low BMD (lumbar spine: T-score -5.2, Z-score -4.3, neck of femur: T-score -4.0, Z-score -3.0). These features strongly suggested osteoporosis pseudoglioma syndrome (OPPG); however, LRP5 screening was negative. Exome sequencing showed both women carried a missense CTNNB1 likely pathogenic variant (c.1723G>A; pGly575Arg, not present in gnomAD, affecting a highly conserved base, predicted deleterious by multiple in silico tools). CTNNB1 variants can cause autosomal dominant FEVR, with variable expressivity and penetrance; and have been associated with autism, developmental delay, and intellectual disability. Association of CTNNB1 pathological variants and bone disease in humans has not been described previously, although common variants in this locus are associated with BMD. CTNNB1 codes for ß-catenin which, along with LRP5, forms part of the canonical Wnt signalling pathway critical for normal skeletal development. ß-catenin stabilisation and knockout causes osteopetrotic and osteopaenic phenotypes respectively. LRP5 mutations are an established cause of OPPG, usually considered a recessive condition. However, heterozygous parents of children with OPPG have low BMD. Conversely, LRP5 variants can cause isolated FEVR. This the first report of a bone phenotype in patients with FEVR due to a CTNNB1 mutation, representing a novel autosomal dominant cause of OPPG. Whether pathogenic variants can cause an isolated osteogenesis imperfecta syndrome remains unknown.