Osteoporosis-pseudoglioma syndrome: description of 9 new cases and beneficial response to bisphosphonates.

Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder of severe juvenile osteoporosis and congenital blindness, due to mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Approximately fifty cases of OPPG have been reported. We report 9 new cases of OPPG, in three related nuclear families of Conservative Mennonites in Pennsylvania. All 9 children with OPPG were blind and had osteoporosis. Four of six parents had low bone mineral density (BMD) or osteoporosis; 2 were normal. Sequence analysis from genomic DNA revealed homozygosity for a nonsense mutation of exon 6 of LRP5 (W425X) in four OPPG cases tested in families A and C. In family B, OPPG cases were compound heterozygotes for the exon 6 W425X LRP5 mutation and a second exon 6 mutation (T409A); bone phenotype was milder than in family A. Neither of these mutations was present in an unrelated normal. The four treated OPPG patients all responded to bisphosphonates (duration 1.5-6.5 years) with improvement in Z-scores. One patient had a negligible response to teriparatide. In summary, we report 9 new cases of OPPG due to two novel LRP5 mutations, note a milder bone phenotype but similar ocular phenotype in LRP5 W425X/T409A compound heterozygotes than in W425X homozygotes and describe positive response to bisphosphonate treatment in four cases.