Osteoporosis-Pseudoglioma Syndrome

A number sign (#) is used with this entry because osteoporosis-pseudoglioma syndrome is caused by homozygous or compound heterozygous mutation in the gene encoding low density lipoprotein receptor-related protein-5 (LRP5; 603506) on chromosome 11q13.

Clinical Features

Bianchine et al. (1972) described 3 families. One of the patients, who had earlier been reported by Bianchine and Murdoch (1969), had had many fractures, suggesting osteogenesis imperfecta. In addition, at the age of a few weeks, presumed retinoblastoma was discovered in each eye. Enucleation was performed after preparatory irradiation. Histology showed pseudoglioma.

Neuhauser et al. (1976) reported a sibship of 3 sisters and 2 brothers who showed osteoporosis of variable severity. The propositus had incapacitating deformities following numerous fractures. Four of the sibs, including 3 with frequent fractures, were blind from infancy, and 2 had mild mental retardation.

Briard and Frezal (1976) suggested that muscular hypotonia and ligamentous laxity are integral features and that intelligence is normal in most cases. Cases such as that of Meyer (1955) may have been instances of this disorder.

Beighton et al. (1985) gave the designation ocular form of osteogenesis imperfecta to the disorder they observed in 4 brothers and a nephew and niece of theirs (related as first cousins). In addition to severe osteogenesis imperfecta, they had blindness due to hyperplasia of the vitreous, corneal opacity, and secondary glaucoma. Robinow (1985), Brude (1986), and Superti-Furga et al. (1986) suggested that this is really the osteoporosis-pseudoglioma syndrome. Two obligate heterozygotes in the family described by Superti-Furga et al. (1986) had had 3 fractures each and had osteoporosis, suggesting the possibility of clinical expression of this recessive gene in heterozygotes (Superti-Furga, 1989). Frontali and Dallapiccola (1986) likewise concluded that Beighton's ocular osteogenesis imperfecta is osteoporosis-pseudoglioma syndrome, and Beighton (1986) acknowledged the diagnosis.

Teebi et al. (1988) described OPS in 2 brothers and a sister whose parents were phenotypically normal first cousins. All 3 sibs had the additional feature of ventricular septal defect. Somer et al. (1988) described affected brother and sister from consanguineous parents in a Finnish kindred. De Paepe et al. (1993) reported the cases of 2 unrelated patients who were single offspring of nonconsanguineous, healthy parents. One, a 17-year-old girl, had serious visual impairment since birth. Retrolental masses were demonstrated echographically. The eye abnormality had been diagnosed as Reese retinal dysplasia (266400). She was severely dwarfed and had major skeletal deformities resulting in inability to walk after age 2 years. The second patient was an 18-year-old girl with unilateral neonatal blindness, short stature, and deformities, mainly of pelvis and lower limbs. Visual acuity was decreased in the right eye and even light perception was completely absent on the left. At the age of 16 years, vision in the right eye worsened as a result of a vitreous hemorrhage and persistence of the primary vitreous was noted. Furthermore, a retrolental dense mass was documented ultrasonographically in the right eye. Skeletal x-rays demonstrated the clinical variability in this disorder. Collagen studies yielded normal results in both patients, thus differentiating it from severe osteogenesis imperfecta, which it resembled.

Inheritance

The osteoporosis-pseudoglioma syndrome is inherited as an autosomal recessive trait (Neuhauser et al., 1976).

Population Genetics

From a review of published cases, Frontali et al. (1985) suggested that OPS may be more frequent in Mediterranean countries.

Mapping

Gong et al. (1996) analyzed 16 DNA samples (7 affected individuals) from 3 different consanguineous kindreds with OPS. Using a combination of traditional linkage analysis and homozygosity mapping, they assigned the OPS locus to 11q12-q13. Studies in 10 additional families of varying ethnic background narrowed the candidate region to a 13-cM interval between D11S1298 and D11S971. The maximum combined lod score was 5.99 at theta of zero with marker D11S987. Gong et al. (1996) found that the most likely location of the OPS gene is in a 3-cM region between GSTP1 (134660) and D11S1296. Their data supported locus homogeneity and provided no evidence of a founder effect.

Molecular Genetics

Gong et al. (2001) showed that LRP5 affects bone mass accrual during growth and identified homozygous mutations in the LRP5 gene that cause OPPG (see, e.g., 603506.0001-603506.0012). They found that obligate carriers of mutant LRP5 genes had reduced bone mass when compared to age- and gender-matched controls.

Using standard PCR-based sequencing, Narumi et al. (2010) analyzed the LRP5 gene in 4 male Japanese patients with typical skeletal and ocular features of OPPG and identified compound heterozygosity for 1 nonsense and 4 missense mutations in 3 of the patients (603506.0025 and 603506.0029-603506.0032). In the fourth patient, they identified only heterozygosity for a splice site mutation (603506.0033) by sequencing; however, using custom-designed oligonucleotide tiling array CGH targeted to a 600-kb genomic region harboring LRP5, Narumi et al. (2010) identified a 7.2-kb microdeletion within the LRP5 gene (603506.0034) on the patient's second allele.