Clinical and radiological characteristics of two patients with osteoporosis–pseudoglioma syndrome caused by a pathogenic homozygotic variant in the LRP5 gene

BACKGROUND: Osteoporosis–pseudoglioma syndrome (OMIM #259770) is an ultrarare autosomal recessive disease characterized by congenital or infant blindness, severe osteoporosis, and spontaneous bone fractures. The syndrome is caused by pathogenic variants in the LRP5 gene, which encodes a protein involved in the transmission of signals in the Wnt/β-catenin signaling pathway. To date, 77 pathogenic variants associated with osteoporosis–pseudoglioma syndrome have been registered in LRP5, mainly localized in the second and third beta-propeller domains of the protein, which have a high affinity for the Wnt ligand. CLINICAL CASES: Two siblings presented with clinical manifestations of osteoporosis–pseudoglioma syndrome caused by a pathogenic homozygous missense variant c.1481GA (p.Arg494Gln) in LRP5. The phenotype of the patients was characterized by a combination of blindness, low bone-mineral density, short stature, and fractures and deformities of long tubular bones and the spine. DISCUSSION: The rarity of the osteoporosis–pseudoglioma syndrome and the similarity of the clinical manifestations of various skeletal disorders and their genetic heterogeneity lead to a late diagnosis and treatment. CONCLUSIONS: We are the first to present the clinical, radiological, and genetic characteristics of two siblings with clinical manifestations of osteoporosis–pseudoglioma syndrome. Its rarity necessitates detailed description of the clinical and genetic characteristics of this syndrome. Molecular genetic testing is an important part of a comprehensive diagnosis.