title: Osteoporosis-pseudoglioma syndrome: description of 9 new cases and beneficial response to bisphosphonates.
abstract: 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.
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, USA. estreete@medicine.umaryland.edu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Streeten
authors.forename: Daniel
authors.initials: D
authors.lastname: McBride
authors.forename: Eric
authors.initials: E
authors.lastname: Puffenberger
authors.forename: Marc E
authors.initials: ME
authors.lastname: Hoffman
authors.forename: Toni I
authors.initials: TI
authors.lastname: Pollin
authors.forename: Patrick
authors.initials: P
authors.lastname: Donnelly
authors.forename: Paul
authors.initials: P
authors.lastname: Sack
authors.forename: Holmes
authors.initials: H
authors.lastname: Morton
mesh_terms: D000293:Adolescent; D000328:Adult; D015519:Bone Density; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004164:Diphosphonates / Q000627:therapeutic use*; D005260:Female; D005910:Glioma / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D010024:Osteoporosis / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D010375:Pedigree; D010641:Phenotype
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates