Pediatric Rheumatology Online Journal → August 2003 → Bone: Miscellaneous Topics → Abstract #152

A NOVEL, HOMOZYGOUS, 2-BASE PAIR DELETION IN THE LRP5 GENE CAUSING OSTEOPOROSIS PSEUDOGLIOMA SYNDROME

D. Wenkert,¹ S. Mumm,^1,2 J. Hagen,² M. P. Whyte.^1,2

¹Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St. Louis, MO, United States; ²Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, United States

Osteoporosis pseudoglioma syndrome (OPPG) is an autosomal recessive disorder caused by inactivating mutations in the gene encoding low density, lipoprotein receptor-related protein 5 (LRP5). Clinical features include early-onset blindness ("retinal dysplasia" within the first few months of life, or phthisis bulbi, with calcifications and cataract formation diagnosed after 1 year of age), micro-ophthalmia, osteoporosis with fractures, wormian bones, hypotonia, and developmental delay.
A 1-year-old Caucasian girl of aunt/nephew parentage had no red light reflex at 4 days-of-age. Bilateral retina detachment with persistent fetal retinal vasculature were unexplained. Ophthalmologic surgery preserved light/dark perception. At age 11 months, bilateral distal femur fractures occurred during a fall. She was osteopenic. Our assessment showed microcephaly, micro-ophthalmia, hypotonia, and hyperextensibility. At age 12 months, when a spica cast was removed, compression fractures of T₈ were noted. At 13 months, further compression fractures were noted. Pamidronate infusions were begun. Lipid levels have been normal. Development has been relatively normal.
Mutation analysis of LRP5, including sequencing of exons and intron/exon boundaries, revealed a homozygous 2-base pair deletion (3194_3195delAC) in exon 14. This would cause a frame shift at amino acid 1065 (D1O65fs) and addition of 71 missense amino acids.
OPPG reveals that LPR5 acts significantly in bone accrual. In 2002, a single base pair change in exon 3 of LPR5 was shown to cause an autosomal dominant high-bone mass trait. Deactivating mutations in LPR5 cause OPPG syndrome with 6 homozygous disease-causing frame shift and nonsense mutations in LPR5, as well as 6 heterozygous putative disease causing missense mutations. These mutations were found in a variety of exons but not exon 14. Our patient has a novel, homozygous, 2-base pair deletion in yet another region of LPR5 which is, therefore, important for the normal functioning of the gene product.